Derivatives of benzothiazines, preparation thereof and application thereof as drugs

ABSTRACT

The object of the present invention is benzothiazine derivatives having the capability of inhibiting 11β-HSD1 not only at an enzymatic level but also at a cell level. The compounds of the present invention are of general formula (I). Wherein notably R 1  represents a hydrogen or OR1 represents an ester or an ether. R 2  represents a naphthyl or a 1, 2, 3, 4-tetrahydro-naphthalene or a biphenyl or phenyl pyridine or a substituted phenyl. R 3  represents a methyl or ethyl; R 4  and R′ 4  represent a hydrogen.

The object of the present invention is derivatives of benzothiazine, themethod for making them, the pharmaceutical compositions which containthem and their use as drugs intended for treating and/or preventingdiabetes of type 2, obesity, dyslipidemias, arterial hypertension andatherosclerosis. These compounds may also find use in treating and/orpreventing hyperglycemias, intolerance to glucose, insulin resistance,hypertriglyceridemias, hypercholesterolemias, restenoses,pancreatitises, retinopathies, nephropathies, neuropathies (Reichard etal., N. Engl. J. Med. 1993, 329:304-309), certain types of cancer(Strickler et al., Diabetes Technology & Therapeutics 2001, 3(2):263-274) or glaucomas (Pascale et al., Ophtalmology 2006, 113(7):1081-86).

The present invention also relates to the combinations between thedescribed compounds and other agents used in the treatment of thesepathologies. Indeed, the treatment of pathologies such as diabetes oftype 2 often requires the combined use of several classes of compoundsin order to attain the recommended values of glycemia and to keep itbalanced (Nathan et al., Diabetes Care 2009 32:193-203). Theseassociations may also relate to combined treatments of obesity anddiabetes of type 2 (Grundy et al., Circulation 2005, 112: 2735-2752).

The metabolic syndrome is an early stage of several seriouscardiovascular pathologies. It develops as a consequence ofinsulin-resistance and is characterized by visceral obesity (Després etal., Nature 2006 444(14): 881-87), associated with certain risk factorssuch as intolerance to glucose and certain dyslipidemias which may beassociated with arterial hypertension (Grundy, Nat. Rev. Drug Discov.2006, 5:295-309).

Diabetes of type 2 is a well-documented pathology since the glycemicdisorders are explained by three main mechanisms: a deficiency of thefunction of the Langerhans β islets at the pancreas, a decrease in theuse of glucose at the peripheral tissues and excess production ofglucose by the liver (Monnier et al., Diabetes & Metabolism 2008, 34:207-216). However, in spite of existing treatments, many patientsaffected with diabetes of type 2 do not reach the recommended glycemiatarget values (notably HbA_(1c)). Therefore, there is always a strongdemand for treatments of this pathology based on new mechanisms.

Obesity is an ailment affecting an increasing number of personsworldwide. It is often associated with an increased risk of diabetes oftype 2, of cardiovascular diseases, of cerebro-vascular strokes and ofcertain types of cancer. Obesity therefore represents a major riskfactor for pathologies associated with a high level of morbidity ormortality.

Glucocorticoids (cortisol in humans, corticosterone in rodents) areubiquitous hormones which play a predominant role in the regulation ofenergy metabolism. They promote gluconeogenesis and inhibit insulinsecretion by beta pancreatic cells as well as peripheral recapture ofglucose (Dallman et al., Front Neuroendocrinol. 1993, 14: 303-347).

It was recently demonstrated that 11β-hydroxysteroid dehydrogenases(11β-HSDs. regulated the glucocorticoid levels in certain target tissues(liver, adipous tissue, kidney, brain . . . ). In humans, this mechanismmay cause a local increase in cortisol. At the adipous tissue, this maylead to an increase in the visceral fatty mass due to the effect ofglucocorticoids on the differentiation of pre-adipocytes into adipocytesand lipogenesis; in certain situations, glucocorticoids promotelipolysis and deleterious impacts of free plasma fatty acids at theliver, pancreas, skeletal muscle for example (lipotoxicity). At theliver, this generation of cortisol may cause an increase in glycemiawhich may develop into diabetes of type 2.

Two isoforms of 11β-HSD are known: type 1 and type 2. 11β-HSD2 is mainlylocalized in the kidneys. It catalyses the transformation of activeglucocorticoids into inactive glucocorticoids (cortisol into cortisonein humans) and consequently it is essentially involved in the protectionof the mineralocorticoid receptors (MR) towards activation by cortisol(Edwars et al., Lancet, 1988, 2: 986-989). Conversely, 11β-HSD1predominantly acts like an 11-keto-reductase and transforms inactiveglucocorticoids into active glucocorticoids in the tissues where it isstrongly expressed (liver and adipous tissue). The inhibition of thisenzyme at a hepatic and adipocyte level should therefore be expressed bya reduction of the effects mentioned earlier. Several studies conductedin animals have confirmed the implication of 11β-HSD1 in models ofobesity and/or diabetes. Thus, the expression of 11β-HSD1 is increasedin diabetic Zucker rats and this increase was correlated with theprogression of the pathology (Duplomb et al., Biochem. Biophys. Res.Commun., 2004, 313: 594-599). Mice without any gene coding for 11β-HSD1(KO mice) have proved to be resistant to hyperglycemia caused by obesityor stress (Kotelevtsev Y. et al. PNAS 1997, 94: 14924-14929).Conversely, transgenic mice selectively over-expressing 11β-HSD1 at theadipous tissue developed visceral obesity, insulin-resistant diabetesand hyperlipidemia (Masuzika et al., Science, 2001, 294: 2166-2170).These experimental data emphasize the inhibition advantage of 11β-HSD1as a therapeutic target (Wamil et al., Drug Discovery Today, 2007, 12:504-520)

The compounds of the present invention have the capability ofselectively inhibiting 11β-HSD1 relatively to 11β-HSD2 which should beexpressed in human by beneficial action on diabetes of type 2, obesity,hyperlipidemias, arterial hypertension, atherosclerosis and the whole ofthe pathologies which are associated therewith such as coronary strokes,cerebro-vascular strokes or arteritis of the lower limbs (Wilcox et al.,Stroke, 2007, 38: 865-873; Wilcox et al., Am. Heart J. 2008, 155:712-7).

These compounds are distinguished from the prior art by their differentchemical structure and their remarkable biological property.

The object of the present invention is benzothiazine derivatives havingthe capability of inhibiting 11β-HSD1 not only at an enzyme level butalso at a cell level.

The compounds of the present invention are of the general formula (I):

wherein:R₁ represents:

-   -   Hydrogen; C₁-C₆ alkyl; COR₅; SO₂R₅; CO(CH₂)_(m)R₆;        CO(CH₂)_(m)OR₆; (CH₂)_(m)R₆; (CH₂)_(m)CONR₇R₈; (CH₂)_(m)NR₇R₈;        (CH₂)_(n)OR₆; CHR₇OR₉; (CH₂)_(m)R₁₀        m represents:    -   1 to 6        n represents:    -   2 to 6        R₂ represents:

A phenyl substituted with one or more groups selected from a halogen,C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe, COMe, CMe(OH)CF₃, CH(OH)CF₃, COOR₇,CONR₇R₁₁; a naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenyl,pyridine or a heterocycle different from indole in the case where R₁, R₄and R′₄ represent a hydrogen, either non-substituted or substituted withone or more groups selected from a halogen or C₁-C₆ alkyl, CN, OH, CF₃,OCF₃, OMe, SMe; a cycloalkyl either non-substituted or substituted withOH, CONH₂, SO₂Me, SO₂NH₂; a C₁-C₆ alkyl aryl or cycloalkyl aryl,

Proviso:—the R₂ group is always bound to the carbonyl through a carbonatom.

When R₂ is a phenyl, the COOR₇ substituent is never in the position 4relatively to the carbonyl.

R₃ represents:

Methyl or ethyl

R₄ and R′₄, either identical or different, represent:

Hydrogen; halogen; C₁-C₆ alkyl; CN; CF₃; OCF₃; SMe; OMe; NR₇R₈; SO₂Me

R₅ represents:

C₁-C₆ alkyl; phenyl either non-substituted or substituted with one ormore groups selected from a halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃,SMe; a naphthyl either non-substituted or substituted with one or moregroups selected from halogen or C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe; acycloalkyl either non-substituted or substituted with a CONH₂, SO₂Me,SO₂NH₂, heteroaryl either non-substituted or substituted with one ormore groups selected from halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe

R₆ represents:

Hydrogen; C₁-C₆ alkyl; phenyl either non-substituted or substituted withone or more groups selected from halogen, C₁-C₆ alkyl, CN, OH, CF₃,OCF₃, SMe; a naphthyl or heterocycle, either non-substituted orsubstituted with one or more groups selected from halogen or C₁-C₆alkyl, CN, OH, CF₃, OCF₃, SMe; a cycloalkyl either non-substituted orsubstituted with CONH₂, SO₂Me, SO₂NH₂

R₇ represents:

Hydrogen, C₁-C₆ alkyl

R₈ represents:

Hydrogen, C₁-C₆ alkyl, phenyl either non-substituted or substituted withone or more groups selected from halogen, C₁-C₆ alkyl, CN, OH, CF₃,OCF₃, SMe; a naphthyl or heterocycle, either non-substituted orsubstituted with one or more groups selected from halogen, C₁-C₆ alkyl,CN, OH, CF₃, OCF₃, SMe; a cycloalkyl either non-substituted orsubstituted with CONH₂, SO₂Me, SO₂NH₂

R₇ and R₈ taken together may form a cycle of 4-6 members with thenitrogen atom to which they are bound and which may contain one or moreheteroatoms selected from N, S or O and may be either non-substituted orsubstituted with one or more groups selected from C₁-C₆ alkyl, C₁-C₆alkyl aryl or aryl.

R₉ represents:

COOMe, COOEt

R₁₀ represents:

Halogen, COOH, COOR_(S)

R₁₁ represents:

Hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl cycloalkyl, cycloalkyl, aryl, C₁-C₆alkyl aryl

as well as their stereoisomers, salts and solvates acceptable fortherapeutic use.In the foregoing definitions:

All the combinations of substituents or of variables are possibleinsofar that they lead to stable compounds.

The term

halogen

represents fluorine, chlorine, bromine or iodine.

The term

alkyl

represents saturated or unsaturated linear or branched, aliphatichydrocarbon chains and comprising the specified number of carbon atoms.

The term

cycloalkyl

represents cyclic or polycyclic hydrocarbon chains comprising from 3-12carbon atoms. As an example, mention may be made of adamantyl,cyclohexyl.

The term

aryl

represents any monocyclic or bicyclic carbon ring which may contain upto 7 atoms per ring and in which at least one of the rings is anaromatic ring. As an example, mention may be made of phenyl, biphenyl,naphthyl.

The term

heteroaryl

either represents a stable monocycle containing 5-7 atoms or a stablebicycle containing 8-11 atoms, unsaturated and consisting of carbonatoms and of one to four heteroatoms selected from N, O or S. As anexample mention may be made of a furane, thiophene, pyridine,benzothiophene.

The term

heterocycle

either represents a stable monocycle containing from 5-7 atoms or astable bicycle containing 8-11 atoms which may be either saturated orunsaturated, and consisting of carbon atoms and of one to fourheteroatoms selected from N, O or S. Are also included in the bicycledefinition, monocyclic heterocycles condensed with a benzene ring exceptfor indole when in formula I, the radicals R₁, R₄ and R′₄ representhydrogen. As an example, mention may be made of furane, pyrrole,thiophene, thiazole, isothiazole, oxadiazole, imidazole, oxazole,isoxazole, pyridine, pyrimidine, quinazoline, quinoline, quinoxaline,benzofurane, benzothiophene, indoline, indolizine, benzothiazole,benzothienyl, benzopyrane, benzoxazole, benzo[1,3]dioxole,benzoisoxazole, benzimidazole, chromane, chromene, dihydrobenzofurane,dihydrobenzothienyl, dihydroisoxazole, isoquinoline,dihydrobenzo[1,4]dioxin, imidazo[1,2-a]pyridine, furo[2,3-c]pyridine,2,3-dihydro-1H-indene, [1,3]dioxolo[4,5-c]pyridine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,tetrahydronaphthalene, benzo[b][1,4]oxazine.

By OR₁, being an ester or an ether, is meant in the sense of the presentinvention that R₁ represents: C₁-C₆ alkyl or COR₅ or CO(CH₂)_(m)R₆ orCO(CH₂)_(m)OR₆ or (CH₂)_(m)R₆ or (CH₂)_(m)CONR₇R₈ or (CH₂)_(n)NR₇R₈ or(CH₂)_(n)OR₆ or CHR₇OR₉ or (CH₂)_(m)R₁₀, as defined earlier.

The salts acceptable for therapeutic use of the compounds of the presentinvention comprise the conventional non-toxic salts of the compounds ofthe invention such as those formed from organic or inorganic acids orfrom organic or inorganic bases. As an example, mention may be made ofthe salts derived from inorganic acids such as hydrochloric,hydrobromic, phosphoric, sulfuric acids, and those derived from organicacids such as acetic, trifluoroacetic, propionic, succinic, fumaric,malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic,toluenesulfonic, methanesulfonic, stearic, lactic acids. As an example,mention may be made of the salts derived from inorganic bases such assoda, potash or calcium hydroxide and the salts derived from organicbases such as lysine or arginine.

These salts may be synthesized from the compounds of the inventioncontaining a basic of acid portion and the corresponding acids or basesaccording to conventional chemical methods.

The solvates acceptable for therapeutic use of the compounds of thepresent invention comprise conventional solvates such as those formedduring the last step of preparation of the compounds of the inventionbecause of the presence of solvents. As an example, mention may be madeof the solvates due to the presence of water or ethanol.

All the stereoisomers including all the optical isomers of the compoundsof general formula (I) are also part of the present invention as well astheir mixture in a racemic form.

According to a particular feature of the invention, the compounds ofgeneral formula (I) are those for which:

-   -   R₂ represents: A phenyl substituted with one or more groups        selected from halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe; a        naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, or        heterocycle different from indole in the case when R₁, R₄ and        R′₄ represent a hydrogen atom, either non-substituted or        substituted with one or more groups selected from a halogen or        C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, OMe, SMe; a cycloalkyl either        non-substituted or substituted with CONH₂, SO₂Me, SO₂NH₂;

With the proviso: the group R₂ is always bound to the carbonyl through acarbon atom.

-   -   R₄ and R′₄, either identical or different, represent: hydrogen;        halogen; C₁-C₆ alkyl; CN; CF₃; OCF₃; SMe; OMe; NR₇R₈;    -   R₈ represents:

A hydrogen, C₁-C₆ alkyl, a phenyl either non-substituted or substitutedwith one or more groups selected from a halogen, C₁-C₆ alkyl, CN, OH,CF₃, OCF₃, SMe; a naphthyl, or a heterocycle, either non-substituted orsubstituted with one or more groups selected from a halogen, C₁-C₆alkyl, CN, OH, CF₃, OCF₃, SMe; a cycloalkyl either non-substituted orsubstituted with CONH₂, SO₂Me, SO₂NH₂

R₇ and R₈ taken together may form a ring with 4-6 members with thenitrogen atom to which they are bound and which may contain one or moreheteroatoms selected from N, S or O and may either be non-substituted orsubstituted with one or more groups selected from a C₁-C₆ alkyl or aryl,with R₁ as defined earlier or as defined hereafter.

According to an embodiment of the invention, the compounds of generalformula (I) are those for which R₁ represents a hydrogen.

According to another embodiment of the invention, the compounds ofgeneral formula (I) are those for which OR₁ represents an ester or anether, with R₁ representing a C₁-C₆ alkyl or COR₅ or CO(CH₂)_(m)R₆ orCO(CH₂)_(m)OR₆ or (CH₂)_(m)R₆ or (CH₂)_(m)CONR₇R₈ or (CH₂)_(n)NR₇R₈ or(CH₂)_(m)OR₆ or CHR₇OR₉ or (CH₂)_(m)R₁₀.

According to a particular embodiment of the invention OR₁ represents anester, with R₁ representing COR₅ or CO(CH₂)_(m)R₆ or CO(CH₂)_(m)OR₆.

The object of the present invention also relates to the compounds ofgeneral formula (I) for which R₂ represents a naphthyl or a1,2,3,4-tetrahydro-naphthalene or biphenyl or a phenyl pyridine eithernon-substituted or substituted with one or more groups selected from ahalogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, OMe, SMe; or a phenylsubstituted with one or more halogens, CN, CF₃ or C₁-C₆ alkyl.

According to an embodiment of the invention, the compounds of generalformula (I) are those for which R₄ and R′₄ represent a hydrogen.

Among the compounds of general formula (I) belonging to the presentinvention, an appreciated class of compounds corresponds to thecompounds of general formula (I) wherein R₁ is a hydrogen and R₂ is anaphthyl or else a 1,2,3,4-tetrahydro-naphthalene.

Also, the present invention relates to the compounds of general formula(I) wherein OR₁ represents an ester or an ether and R₂ is a naphthyl orelse a 1,2,3,4-tetrahydro-naphthalene.

Another appreciated class of compounds corresponds to the compounds ofgeneral formula (I) wherein R₁ is a hydrogen and R₂ is a phenylsubstituted with one or more halogens, CN, CF₃ or C₁-C₆ alkyl.

Another appreciated class of compounds corresponds to the compounds ofgeneral formula (I) wherein R₁ is a hydrogen and R₂ is a biphenyl or aphenyl pyridine, either non-substituted or substituted as defined in thedescription of general formula (I).

Also, the present invention relates to the compounds of general formula(I) wherein OR₁ represents an ester or an ether and R₂ is a phenylsubstituted with one or more halogen, CN, CF₃ or C₁-C₆ alkyl.

Another appreciated class of compounds corresponds to the compounds ofgeneral formula (I) wherein OR1 represents an ester or an ether and R2is a biphenyl or a phenyl pyridine non-substituted or substituted asdefined in the description of the general formula (I).

The present invention also relates to the preparation of the compoundsof general formula (I) by general methods described in the followingsynthesis schemes if necessary completed with all the standardmanipulations described in the literature or well-known to one skilledin the art or else still exemplified in the experimental part.

Scheme 1 illustrates the first general method which may be used forpreparing the compounds of general formula (Ia). In the general formulaeabove R₂, R₃, R₄ and R′₄, are defined as in the previous description ofthe general formula (I) and R₁ is equal to hydrogen. X may represent aleaving group such as for example Cl, Br, I, OSO₂CH₃, OSO₂CF₃ orO-tosyl. In this case, the reaction with the compound of general formula(II) will be conducted in the presence of an inorganic base such as forexample NaH in a polar anhydrous solvent such as THF or DMF at atemperature comprised between −20° and 100° C. The intermediate ofgeneral formula (III) is transformed into an intermediate of generalformula (IV) by a rearrangement reaction in the presence of a base suchas for example MeONa, EtONa in a polar anhydrous solvent such as MeOH orEtOH (possibly mixed with an apolar solven such as toluene) at atemperature comprised between 25° and 100° C. The intermediate ofgeneral formula (IV) is transformed into a product of general formula(Ia) by reaction with R₃Y wherein Y may represent a leaving group suchas for example Cl, Br, I, OSO₂CH₃, OSO₂CF₃ or O-tosyl and R₃ is definedas earlier. In this case, the reaction with the compound of generalformula (IV) will be conducted in the presence of an inorganic base suchas for example NaH in a polar anhydrous solvent such as THF or DMF at atemperature comprised between −20° and 100° C.

Scheme 2 illustrates the general method which may be used for preparingthe compounds of general formula (Ib). In the general formulae below,R₁, R₂, R₃, R₄ and R′₄, are defined as in the previous description ofthe general formula (I) except that R₁ is different from a hydrogen.

The intermediate of general formula (Ia) is transformed into a compoundof general formula (Ib) by reaction with R₁—Z. When R₁ represents aC₁-C₆ alkyl, (CH₂)_(m)R₆, (CH₂)_(m)CONR₇R₈, (CH₂)_(n)NR₇R₈,(CH₂)_(n)OR₆, CHR₇OR₉ or (CH₂)_(m)R₁₀ with R₆, R₇, R₈, R₉, R₁₀, m and ndefined as in the previous description of the general formula (I),except that R₁₀ does not represent an acid, and Z is a leaving groupsuch as for example Cl, Br, I, OSO₂CH₃, OSO₂CF₃ or O-tosyl, the reactionwith the enol of general formula (Ia) may be conducted in the presenceof an organic or inorganic base such as for example Et₃N, iPr₂NEt, NaH,pyridine, Cs₂CO₃, K₂CO₃ in a polar anhydrous solvent such as THF, DMF,DMSO, acetone at a temperature comprised between −20° and 140° C.,either in the presence or not of a salt as a catalyst and which may beKI, Bu₄NI, LiI, AgBF₄, AgClO₄, Ag₂CO₃, KF, Bu₄NF or CsF. The reactionmay also be conducted in a

sealed or threaded tube

heated by heat energy or microwave energy, at temperatures comprisedbetween 80 and 180° C. Z may also represent an alcohol. In this case,the reaction with the intermediate (Ia) will be of the

Mitsunobu

type and may be conducted in the presence of diethylazodicarboxylate(DEAD) and of triphenylphosphine in a polar anhydrous solvent such asTHF at a temperature comprised between 0 and 60° C. When R₁ representsCOR₅, SO₂R₅ or CO(CH₂)_(m)R₆ with R₅, R₆ and m defined as in theprevious description of the general formula (I) then Z may represent achlorine. In this case, the reaction with the enol of general formula(Ia) boils down to the reaction between an acid chloride and a sulfonylchloride and an alcohol. This reaction may be conducted in the presenceof an organic or inorganic base such as for example Et₃N, iPr₂NEt, NaH,pyridine, Cs₂CO₃, K₂CO₃ in a polar anhydrous solvent such as THF, DMF,DMSO, dichloromethane at a temperature comprised between −20° and 140°C. When R₁ represents COR₅, CO(CH₂)_(m)R₆ or CO(CH₂)_(m)OR₆ with R₅, R₆and m defined as in the previous description of the general formula (I)then Z may also represent a hydroxyl. In this case, the reaction withthe enol of general formula (Ia) boils down to the reaction between anacid and an alcohol. This reaction may be conducted by methods andtechniques well-known to one skilled in the art. A particularlyappreciated method consists of producing this condensation in thepresence of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), of3-hydroxy-1,2,3-benzotriazin-4(3H)-one, of a tertiary amine such asdiisopropylethylamine, in a polar aprotic solvent such asdichloromethane, at a temperature comprised between −15° C. and 40° C.

Scheme 3 illustrates the general method which may be used for preparingthe compounds of general formula (Ic) wherein R₁ represents(CH₂)_(n)NR₇R₈ or (CH₂)_(n)OR₆ with R₆, R₇, R₈, n and R₂, R₃, R₄ and R′₄defined as in the previous description of general formula (I). Theintermediate of general formula (Ia) is transformed into an intermediateof general formula (V) by reaction with a reagent of general formulaX(CH₂)_(n)X′ wherein X and X′ represent a leaving group either identicalor different such as for example Cl, Br, I, OSO₂CH₃, OSO₂CF₃ or O-tosyland n is defined as earlier.

The reaction between this reagent and the enol of general formula (Ia)for leading to the intermediate of general formula (V) may be conductedin the presence of an organic or inorganic base such as for exampleEt₃N, iPr₂NEt, NaH, pyridine, Cs₂CO₃, K₂CO₃ in a polar anhydrous solventsuch as THF, DMF, DMSO, acetone at a temperature comprised between −20°and 140° C., either in the presence or not of a salt as a catalyst andwhich may be KI, Bu₄NI, LiI, AgBF₄, AgClO₄, Ag₂CO₃, KF, Bu₄NF or CsF.This reaction may also be conducted without any solvent, with a largeexcess of reagent X(CH₂)_(n)X′. The reaction may also be conducted in a

sealed or threaded tube

heated by heat energy or microwave energy, at temperatures comprisedbetween 80 and 180° C. X or X′ may also represent an alcohol. In thiscase, the reaction with the intermediate (V) will be of the

Mitsunobu

type and may be conducted in the presence of diethylazodicarboxylate(DEAD) and of triphenylphosphine in a polar anhydrous solvent such asTHF at a temperature comprised between 0 and 60° C.The intermediate of general formula (V) is transformed into a product ofgeneral formula (Ic) by reaction with HNR₇R₈ or HOR₆ wherein R₆, R₇ andR₈ are defined as in the previous description of the general formula(I). This reaction may be conducted in the presence of an organic orinorganic base such as for example Et₃N, iPr₂NEt, NaH, pyridine, Cs₂CO₃,K₂CO₃ in a polar anhydrous solvent such as THF, DMF, DMSO, acetone at atemperature comprised between −20° and 140° C., either in the presenceor not of a solvent as a catalyst and which may be KI, Bu₄NI, LiI,AgBF₄, AgClO₄, Ag₂CO₃, KF, Bu₄NF or CsF. The selection of theexperimental conditions and of the reagents for conducting this reactionof course depends on the nature of the substituents R₆, R₇ and R₈ andwill be performed according to the methods and techniques well-known toone skilled in the art.

Scheme 4 illustrates the general method which may be used for preparingthe compounds of general formula (Id) wherein R₁ represents(CH₂)_(m)CONR₇R₈ with R₇, R₈, m and R₂, R₃, R₄ and R′₄, defined as inthe previous description of general formula (I).

The intermediate of general formula (Ia) is transformed into anintermediate of general formula (VI) by reaction with a reagent ofgeneral formula Y(CH₂)_(m)COOY′ wherein Y represents a leaving groupsuch as for example Cl, Br, I, OSO₂CH₃, OSO₂CF₃ or O-tosyl, m is definedas earlier and Y′ represents a C₁-C₄ alkyl radical. This reaction may beconducted in the presence of an organic or inorganic base such as forexample Et₃N, iPr₂NEt, NaH, pyridine, Cs₂CO₃, K₂CO₃ in a polar anhydroussolvent such as THF, DMF, DMSO, acetone at a temperature comprisedbetween −20° and 140° C., either in the presence or not of a salt as acatalyst and which may be KI, Bu₄NI, LiI, AgBF₄, AgClO₄, Ag₂CO₃, KF,Bu₄NF or CsF. The reaction may also be conducted in a

sealed or threaded tube

heated by heat energy or microwave energy, to temperatures comprisedbetween 80 and 180° C. The intermediate of general formula (VI) istransformed into an intermediate of general formula (VII) by reactionwith an inorganic base such as for example NaOH, KOH, LiOH in a polarsolvent such as methanol, ethanol, THF and water, at a temperaturecomprised between 20° and 80° C. The obtained carboxylic acid (VII) mayreact with an amine in order to lead to the compounds of general formula(Id). This reaction may be conducted by the methods and techniqueswell-known to one skilled in the art. A particularly appreciated methodconsists of condensing these 2 entities in the presence of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), of3-hydroxy-1,2,3-benzotriazin-4(3H)-one, of a tertiary amine such asdiisopropylethylamine, in a polar aprotic solvent such asdichloromethane or DMF, at a temperature comprised between −15° C. and50° C. Or further, as an example, by usingbenzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate(BOP) in the presence of 1-hydroxybenzotriazole, of a tertiary aminesuch as diisopropylethylamine, in a polar solvent such as DMF, CH₂Cl₂ orDMSO at a temperature comprised between 10° and 50° C. Anotherparticularly appreciated method consists of transforming the carboxylicacid into an acid chloride by reaction with oxalyl chloride or thionylchloride in the absence or in the presence of a base such as pyridine ortriethylamine with or without a solvent such as toluene ordichloromethane at a temperature comprised between 20 and 100° C. Thisacid chloride may then react with the amine HNR₇R₈ in the presence of abase such as pyridine or triethylamine in a solvent such asdichloromethane at a temperature comprised between 0 and 100° C.

Scheme 5 illustrates the general method which may be used fortransforming the compounds of general formula (Ie) wherein R₄ representsa fluorine and R₂, R₃ and R′₄ are defined as in the previous descriptionof the general formula (I) into compounds of general formula (If)wherein R₄ represents NR₇R₈ with R₇, R₈ and R₂, R₃ and R′₄ defined as inthe previous description of the general formula (I).

The compounds of general formula (Ie) may be transformed into compoundsof general formula (If) by reaction with an amine of general formulaHNR₇R₈ in the presence of an organic or inorganic base such as forexample Et₃N, iPr₂NEt, NaH, Cs₂CO₃, K₂CO₃ in a polar anhydrous solventsuch a DMF, DMSO at a temperature comprised between 20° and 140° C.Scheme 6 illustrates the general method which may be used fortransforming the compounds of general formula (Ig) wherein R₃, R₄ andR′₄ are defined as in the previous description of the general formula(I) and wherein R₂ represents a phenyl substituted with a group Xrepresenting a bromine, chlorine or an OTf, into compounds of generalformula (Ih) where R₂ represents a biphenyl or a phenyl pyridine eithersubstituted or not and wherein R₃, R₄ and R′₄ are defined as in theprevious description of the general formula (I).

The compounds of general formula (Ig) may be transformed into compoundsof general formula (Ih) by a Suzuki type reaction with a boronic acid inthe presence of an organic or inorganic base such as for example Et₃N,NMP, iPr₂NEt, NaH, Cs₂CO₃, K₂CO₃, K₃PO₄ with a catalyst such as forexample palladium acetate, palladium tetrakis triphenylphosphine,tris(dibenzilideneacetone) dipalladium in a polar solvent such as forexample acetone, methyl ethyl ketone, ethanol, DME, water, dioxane, andoptionally in the presence of a phosphine such as triphenylphosphine ortricyclohexylphosphine at a temperature comprised between 20° and 140°C.Scheme 7 illustrates the general method which may be used fortransforming the compounds of general formula (II) wherein R₃, R₄ andR′₄ are defined as in the previous description of general formula (I)and wherein R₂ represents a phenyl substituted with a CN group in theortho or meta position into compounds of general formula (Ij) wherein R₂represents a phenyl substituted with a carboxylic acid in the ortho ormeta position and then into compounds of general formula (Ik) wherein R₂represents a phenyl substituted with an amide of formula CONR₇R₁₁ andwherein R₃, R₄, R₇, R₁₁ and R′₄ are defined as in the previousdescription of the general formula (I).

The compounds of general formula (II) may be transformed into compoundsof general formula (Ij) by treatment with an inorganic base such as forexample NaOH, KOH, LiOH in a polar solvent such as ethanol, methanol,THF, water at a temperature comprised between 20° and 140° C. followedby acidification by treatment with an acid such as HCl, H₂SO₄, HCOOH.The compounds of general formula (Ij) may be transformed into compoundsof general formula (Ik) by reaction with an amine of formula HNR₇R₁₁.This reaction may be conducted with methods and techniques well-known toone skilled in the art. A particularly appreciated method consists ofcondensing these 2 entities in the presence of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC), of3-hydroxy-1,2,3-benzotriazin-4(3H)-one, of a tertiary amine such asdiisopropylethylamine, in a polar aprotic solvent such asdichloromethane or DMF, at a temperature comprised between −15° C. and50° C. Or further, as an example, by usingbenzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate(BOP) in the presence of 1-hydroxybenzotriazole, of a tertiary aminesuch as diisopropylethylamine, in a polar solvent such as DMF, CH₂Cl₂ orDMSO at a temperature comprised between 10° and 50° C. Anotherparticularly appreciated method consists of transforming the carboxylicacid into an acid chloride by reaction with oxalyl chloride or thionylchloride in the absence or in the presence of a base such as pyridine ortriethylamine with or without a solvent such as toluene ordichloromethane at a temperature comprised between 20 and 100° C. Thisacid chloride may then react with the amine HNR₇R₁₁ in the presence of abase such as pyridine or triethylamine in a solvent such asdichloromethane at a temperature comprised between 0 and 100° C.

When it is desired to isolate a compound of general formula (I)containing at least one acid or basic function in the salt state byaddition with a base or an acid, this may be achieved by treating thefree base or acid of general formula (I) (wherein at least one acid orbasic function exists) with a suitable base or acid, preferably in anequivalent amount.

The examples which follow illustrate the invention without howeverlimiting the scope thereof.

Note: for the whole of the following compounds (except if mentionotherwise) the HPLC purities were determined under the followingconditions:Column Waters XTerra MS C₁₈, 4.6×50 mm, 5 μm, λ=220 nm, Gradient 100%H₂O (+0.05% TFA) at 100% CH₃CN (+0.05% TFA) in 6 minutes, and then 1minute at 100% CH₃CN (+0.05% TFA). Pump Waters 600E, flow rate of 3ml/min.

EXAMPLE 1(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

EXAMPLE 1A2-(2-(naphthalen-2-yl)-2-oxoethyl)benzo[d]isothiazol-3(2H)-one-1,1-dioxide

The saccharin (25 g, 136 mmol) and DMF (350 mL) are introduced into athree-neck flask equipped with a thermometer and a condenser. The mediumis inertized by a vacuum/nitrogen succession (3×). Sodium hydride (6 g,150 mmol) is slowly added, followed by2-bromo-1-(naphthalen-2-yl)ethanone (37.4 g, 150 mmol). The reactionmedium is heated to 65° C. for 4 hours, and then cooled to roomtemperature. The formed precipitate is filtered, rinsed with water anddried until constant weight for obtained 37 g of the product 1A as apale being solid (HPLC: RT=4.97 min, 100%). A second product batch isobtained by adding water into the filtrate. The formed precipitate isfiltered, rinsed with water and then with a minimum of ethyl in order toobtain after drying, 10 g of product (HPLC: RT=4.97 min, 93%). Theglobal yield of this reaction is 96%.

¹H NMR, dmso-d₆, δ (ppm): 5.62 (s, 2H); 7.68 (t, 1H); 7.73 (t, 1H);8.00-8.25 (m, 7H); 8.39 (d, 1H); 8.92 (s, 1H).

Mass spectrum (ESI+): m/z 352 (MH⁺, 100%); 369 (MNH₄ ⁺, 24%).

EXAMPLE 1B(4-hydroxy-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

In a two-neck flash equipped with a condenser and under an inertatmosphere, ethanol (165 mL) is introduced followed by slow addition ofsodium cut into thin slices and rinsed with heptane (8 g, 347 mmol). Atthe end of the addition, the reaction medium is heated to 70° C. untilcomplete reaction of the sodium. The reaction is then cooled to roomtemperature, and the compound 1A (47 g, 131 mmol) is added rapidly. Anintense vermilion red and then blood red coloration appears as well as athick precipitate. The reaction medium is heated briefly to 60° C. whereit solidifies. It is then cooled to room temperature and diluted in 500mL of ethyl acetate. A 1N HCl aqueous solution is then added until acanary yellow suspension is obtained. The precipitate is filtered,rinsed with water and a minimum of a 50/50 water/EtOH mixture. It isthen dried in vacuo until it has constant weight in order to obtain theproduct 1B as a canary yellow solid (40.9 g; 88%). HPLC: RT=5.15 min,100%.

¹H NMR, dmso-d₆, δ (ppm): 7.66 (t, 1H); 7.72 (t, 1H); 7.95 (broad s,3H); 8.05 (d, 2H); 8.11 (broad s, 2H); 8.22 (broad s, 1H); 8.64 (s, 1H);9.99 (s, 1H); 15.59 (s, 1H).

Mass spectrum (ESI+): m/z 352 (MH⁺, 100%); 369 (MNH₄ ⁺, 31%).

EXAMPLE 1(1,1-dioxo-4-hydroxy-2-methyl-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

In a two-neck flask under an inert atmosphere, the compound 1B (40.9 g,116 mmol) is dissolved in DMF (409 mL). NaH (6.05 g, 151 mmol) is added.This reaction is slightly exothermic and the reaction medium assumes anintense blood red coloration. Methane iodide (10.8 mL, 174 mmol) isadded and the reaction medium is stirred at room temperature for 2hours. Water (10 mL) is added and the reaction medium is concentrated.The residue is taken up in ethyl acetate and the precipitate isfiltered, washed with water and with a minimum of ethyl acetate (solid1). The filtrate is washed twice with an aqueous solution half-saturatedwith NaCl, and then concentrated until half of the volume is obtainedand filtered. The precipitate (solid 2) is rinsed with a minimum of50/50 EtOAc/Et₂O. The filtrate is concentrated. The residue is filteredon silica (eluent: 50/50 heptane/CH₂Cl₂, and then 25/75 heptane/CH₂Cl₂),in order to obtain after evaporation of the solvents, a yellow powder(solid 3). The 3 solids are collected in order to obtain the product 1as a canary yellow solid (40.1 g; 89%) HPLC: RT=5.65 min, 99%

¹H NMR, dmso-d₆, δ (ppm): 2.65 (s, 3H); 7.66 (t, 1H); 7.72 (t, 1H); 8.00(broad s, 3H); 8.02 (d, 1H); 8.12 (broad s, 3H); 8.22 (broad s, 1H);8.67 (s, 1H).

Mass spectrum (ESI+): m/z 366 (MH⁺, 100%).

Preparation of the sodium salt of4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]-thiazin-3-yl)(naphthalen-2-yl)methanone

A fraction of the compound 1 is dissolved and methanol and treated atroom temperature with 1.05 equivalents of an aqueous 1N soda solution.The reaction medium is concentrated and the solid residue rinsed with amixture of dichloromethane and ethyl ether. The thereby obtained canaryyellow solid is dried in vacuo for several days.

HPLC: RT=11.73 min, 99.71% (column: XBridge C8, 5 μM, 4.6×250 mm(Waters); eluent: CH₃CN/H₂O/KH₂PO₄ 600/400/6.8 g, pH4, 25° C.; 1 mL/min;220 nm)

¹H NMR, dmso-d₆, δ (ppm): 2.61 (s, 3H); 7.50 (broad s, 2H); 7.62 (broads, 2H); 7.65-7.72 (m, 2H); 7.80 (d, 1H); 7.89 (broad s, 2H); 7.93-7.98(m, 2H).

Mass spectrum (ESI+): m/z 366 (MH⁺, 100%).

EXAMPLES 2 TO 12

The compounds 2 to 12 were synthesized according to the procedure usedfor preparing the derivative 1, from saccharin and various2-bromo-1-(alkyl or aryl)ethanones in the first step and from methyliodide or ethyl iodide in the third step. The rearrangement protocol inthe second step is unchanged.

Yld. Mass Ex. ** R Name of the compounds HPLC (3 steps) MH⁺ 2 adamantan-(4-hydroxy-2-methyl-2H- 6.11′ 30% 374 1-yl 1,1-dioxo-benzo[e][1,2] 98.9%thiazin-3-yl) (adamantan- 1-yl)methanone 3 4-methyl-(4-hydroxy-2-methyl-2H- 5.33′ 49% 330 phenyl 1,1-dioxo-benzo[e][1,2] 99%thiazin-3-yl) (4- methylphenyl)methanone 4 4-chloro-(4-hydroxy-2-methyl-2H- 5.43′ 38% 350 phenyl 1,1-dioxo-benzo[e][1,2] 99%thiazin-3-yl) (4- chlorophenyl)methanone 5 4-cyano- (4-hydroxy-2-methyl-4.97′ 82%  339* phenyl 2H-1,1-dioxo-benzo 99% [e][1,2]thiazin-3-yl) (4-cyanophenyl)methanone 6 biphenyl- biphenyl-4-yl-(4-hydroxy- 5.86′ 57%392 4-yl 2-methyl-1,1-dioxo-2H- 98% benzo[e][1,2]thiazin-3- yl)methanone7 2,4- (4-hydroxy-2-methyl- 5.52′ 14% 384 dichloro- 1,1-dioxo-2H- 98%phenyl benzo[e][1,2]thiazin-3- yl) (2,4-dichlorophenyl) methanone *negative ESI (M − H). ** ¹H NMR, dmso-d₆, Ex. 2: 1.72 (broad s, 6 H);2.05 (broad s, 3 H); 2.10 (broad s, 6 H); 2.83 (s, 3 H); 7.91 (broad s,3 H); 8.10 (t, 1 H); 16.1 (s, 1 H). Ex. 5: 2.63 (s, 3 H); 7.99 (s, 3 H);8.11 (s, 4 H); 8.19 (broad s, 1 H); 14.5-15.5 (m, 1 H, exch). Ex. 6:2.70 (s, 3 H); 7.46 (t, 1 H); 7.54 (t, 2 H); 7.82 (d, 2 H); 7.95-8.00(m, 5 H); 8.18-8.23 (m, 3 H); 15.65 (broad s, 1 H, exch). Ex. 7: 2.67(s, 3 H); 7.54-7.64 (m, 2 H); 7.83 (s, 1 H); 7.93 (broad s, 3 H); 8.11(broad s, 1 H); 13.5-14.5 (broad s, 1 H).

Yld. (3 Mass Ex. * R Name of the compounds HPLC steps) (M + H)⁺ 8adamantan- (4-hydroxy-2-ethyl-1, 6.24′ 32% 388 1-yl 1-dioxo-2H-benzo[e]99% [1,2]thiazin-3-yl) (adamantan-1-yl) methanone 9 naphthalen-(4-hydroxy-2-ethyl-1, 5.72′ 55% 380 2-yl 1-dioxo-2H-benzo[e] 99%[1,2]thiazin-3-yl) (naphthalen-2-yl) methanone 10 4-methyl-(4-hydroxy-2-ethyl-1, 5.49′ 40% 344 phenyl 1-dioxo-2H-benzo[e] 99%[1,2]thiazin-3-yl) (4- methylphenyl) methanone 11 4-chloro-(4-hydroxy-2-ethyl-1, 5.58′ 35% 364 phenyl 1-dioxo-2H-benzo[e] 99%[1,2]thiazin-3-yl) (4- chlorophenyl)methanone 12 biphenyl-biphenyl-4-yl-(4- 6.06′ 61% 406 4-yl hydroxy-2-ethyl-1, 99%1-dioxo-2H-benzo [e][1,2]thiazin-3- yl)methanone * ¹H NMR, dmso-d₆, Ex.8: 0.68 (t, 3 H); 1.71 (broad s, 6 H); 2.05 (broad s, 3 H); 2.09 (broads, 6 H); 3.44 (q, 2 H); 7.89 (broad s, 3 H); 8.05 (broad s, 1 H); 15.00(s, 1 H, exch.). Ex. 9: 0.51 (t, 3 H); 3.13 (q, 2 H); 7.66 (t, 1 H);7.72 (t, 1 H); 7.99 (broad s, 3 H); 8.05 (d, 1 H); 8.12 (broad s, 3 H);8.22 (broad s, 1 H); 8.64 (s, 1 H); 15.39 (s, 1 H, exch.). Ex. 11: 0.53(t, 3 H); 3.13 (q, 2 H); 7.71 (d, 2 H); 7.98 (broad s, 3 H); 8.03 (d, 1H); 8.19 (broad s, 1 H). Ex. 12: 0.56 (t, 3 H); 3.18 (q, 2 H); 7.45 (t,1 H); 7.53 (t, 2 H); 7.82 (d, 2 H); 7.94-7.98 (m, 5 H); 8.16 (d, 2 H);8.20-8.21 (m, 1 H); 15.46 (s, 1 H, exch.)

EXAMPLE 13(5-Chloro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

EXAMPLE 13A 2-Chloro-6-sulfamoylbenzoic acid

In a three-neck flask provided with a condenser,3-chloro-2-methylbenzenesulfonamide (13.27 g, 64.5 mmol) is introducedin the presence of 5% soda in water (385 mL). Potassium permanganate(25.5 g, 161 mmol) is slowly added and then the reaction mixture isheated to 100° C. for 4 hours. The reaction is returned to roomtemperature, filtered, acidified up to a pH of 1 and extracted 3 timeswith ethyl acetate. The organic phases are combined, washed once with anaqueous NaCl saturated solution, and then dried on magnesium sulfate,filtered and concentrated in order to obtain the product 13A as a whitesolid (12.87 g; 83%)

HPLC: RT=1.55 min, 98%

¹H NMR, dmso-d₆, δ (ppm): 7.48 (s, 2H, exch.); 7.62 (t, 1H); 7.75 (d,1H); 7.87 (d, 1H); 11-15 (mL, 1H, exch.).

Mass spectrum (ESI−): m/z 234 (M-H⁻, 55%).

EXAMPLE 13B 4-chlorosaccharin

The compound 13A (12.87 g, 54.6 mmol) is introduced into a flaskfollowed by 38.8 mL of concentrated sulfuric acid. The reaction mixtureis stirred at room temperature for 1.5 hours and then poured on amixture of water and ice. The formed precipitate is filtered, rinsedwith water and dried until its weight is constant in order to obtain thecompound 13B as a white solid (9.16 g; 77%).

HPLC: RT=2.57 min, 100%

¹H NMR, dmso-d₆, δ (ppm): 7.91 (broad s, 2H); 8.08 (broad s, 1H).

EXAMPLE 13C4-chloro-2-(2-(naphthalen-2-yl)-2-oxoethyl)benzo[d]isothiazol-3(2H)-one-1,1-dioxide

The compound 13C was synthesized from the compound 13B (2.2 g, 10 mmol)according to the procedure used for preparing the derivative 1A in orderto obtain the compound 13C as a pale beige solid (3.3 g; 84%).

HPLC: RT=5.11 min, 99%

¹H NMR, dmso-d₆, δ (ppm): 5.62 (s, 2H); 7.69 (t, 1H), 7.74 (t, 1H);7.95-8.20 (m, 6H); 8.38 (d, 1H); 8.92 (s, 1H).

Mass spectrum (ESI+): m/z 386 (MH⁺, 100%).

EXAMPLE 13D (5-chloro-1,1-dioxo-4-hydroxy-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 13D was synthesized from the compound 13C (3.3 g, 8.5 mmol)according to the procedure used for preparing the derivative 1B in orderto obtain the compound 13D as a golden yellow solid (1.7 g; 51%).

HPLC: RT=5.3 min, 99%

¹H NMR, dmso-d₆, δ (ppm): 7.68 (t, 1H), 7.72 (t, 1H); 7.85-8.15 (m, 8H);8.59 (s, 1H); 10.11 (s, 1H).

Mass spectrum (ESI+): m/z 386 (MH⁺, 100%).

EXAMPLE 13

The compound 13 was synthesized from the compound 13D (3 g, 7.7 mmol)according to the procedure used for preparing the derivative 1 in orderto obtain the compound 13 as a yellow solid (2.3 g; 70%).

HPLC: RT=5.75 min, 95%

¹H NMR, dmso-d₆, δ (ppm): 2.69 (s, 3H); 7.66 (t, 1H); 7.72 (t, 1H);7.9-8.2 (m, 7H); 8.60 (broad s, 1H); 16.15 (broad s, 1H, exch.).

Mass spectrum (ESI+): m/z 400 (MH⁺, 100%).

EXAMPLE 14(5-Chloro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 14 was synthesized from the compound 13D (1 g, 2.6 mmol)and from iodoethane according to the procedure used for preparing thederivative 1 in order to obtain 805 mg (60%) of the desired product.

HPLC: RT=5.77 min, 81%

A fraction of this product (200 mg) was purified on a column of 12 g ofspherical silica (flow rate 12 mL/min, 100% heptane (2 min),EtOAc/heptane gradient from 0 to 50% (30 min), 50% EtOAc/heptane (5min)), in order to obtain 64 mg of desired product as a yellow solid.

HPLC: RT=5.77 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 0.51 (t, 3H); 3.11 (q, 2H); 7.66 (t, 1H); 7.72(t, 1H); 7.85-8.2 (m, 7H); 8.60 (s, 1H); 15.9 (s, 1H, exch.).

Mass spectrum (ESI+): m/z 414 (MH⁺, 100%).

EXAMPLE 15(6-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

EXAMPLE 15A (6-fluoro-4-hydroxy-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 15A was synthesized from the compound4-fluoro-2-methylbenzenesulfonamide according to the same sequence ofsteps involved in preparing the compound 13D. The product is obtained asa yellow solid with an overall yield of 79%.

HPLC: RT=5.26 min, 96%

¹H NMR, dmso-d₆, δ (ppm): 7.66 (t, 1H); 7.72 (t, 1H); 7.80 (t, 1H);7.94-8.11 (m, 6H); 8.64 (s, 1H); 10.18 (s, 1H, exch.); 15.2 (broad s,1H, exch.).

Mass spectrum (ESI−): m/z 368 (M-H⁻, 100%).

EXAMPLE 15(6-fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 15 was synthesized from the compound 15A (1.5 g, 4 mmol)according to the procedure used for preparing the derivative 1 in orderto obtain 1.47 g (89%) of the desired product as a yellow solid.

HPLC: RT=5.6 min, 93%

A fraction of this product was recrystallized from ethanol in order toobtain 186 mg of compound 15 with greater purity (HPLC: RT=5.6 min,99.4%).

¹H NMR, dmso-d₆, δ (ppm): 2.68 (s, 3H); 7.66 (t, 1H); 7.72 (t, 1H); 7.84(t, 1H); 7.97 (d, 1H); 8.02-8.15 (m, 5H); 8.66 (s, 1H); 15.22 (broad s,1H, exch.).

Mass spectrum (ESI+): m/z 384 (MH⁺, 100%).

EXAMPLE 16(6-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 16 was synthesized from the compound 15A (1.5 g, 4 mmol)and from iodoethane according to the procedure used for preparing thederivative 1 in order to obtain 520 mg (29%) of the desired product as ayellow solid.

HPLC: RT=5.8 min, 91%

A fraction of this product was recrystallized from ethanol in order toobtain 71 mg of compound 16 with greater purity.

HPLC: RT=5.8 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 0.56 (t, 3H); 3.15 (q, 2H); 7.66 (t, 1H); 7.72(t, 1H); 7.82 (t, 1H); 7.97 (d, 1H); 8.00-8.2 (m, 5H); 8.63 (s, 1H);14.95 (broad s, 1H).

Mass spectrum (ESI+): m/z 398 (MH⁺, 100%).

EXAMPLE 17(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2,1-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

EXAMPLE 17A 5-fluoro-2-methylbenzenesulfonamide

5-fluoro-2-methylbenzenesulfonyl chloride (5.00 g, 23.9 mmol) is slowlyadded at 0° C. onto 23 mL of a concentrated ammonia solution. Thereaction medium is then heated to 100° C. for 1 hour and then cooled toroom temperature. The formed precipitate is filtered, rinsed with waterand dried until it has constant weight. The compound 17A is obtained asa white powder (4.55 g; 100%).

HPLC: RT=3.10 min, 96%

¹H NMR, dmso-d₆, δ (ppm): 2.54 (s, 3H); 7.35-7.45 (m, 2H); 7.53 (broads, 2H, exch.); 7.58 (de, 1H).

Mass spectrum (ESI−): m/z 188 (M-H⁻, 100%).

EXAMPLE 17B(7-Fluoro-4-hydroxy-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 17B was synthesized from the compound 17A according to thesame sequence of steps involved in preparing the compound 13D. Theproduct is obtained as a yellow solid with an overall yield of 73%.

HPLC: RT=5.18 min, 98%

¹H NMR, dmso-d₆, δ (ppm): 7.66 (t, 1H); 7.72 (t, 1H); 7.81 (t, 1H); 7.90(d, 1H); 8.04 (d, 2H); 8.11 (broad s, 2H); 8.30 (dd, 1H); 8.63 (s, 1H);10.19 (broad s, 1H); 15.63 (broad s, 1H).

Mass spectrum (ESI−): m/z 368 (M-H⁻, 100%).

Mass spectrum (ESI+): m/z 370 (MH⁺, 100%).

EXAMPLE 17(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 17 was synthesized from the compound 17B (4.00 g, 10.8mmol) according to the procedure used for preparing the derivative 1 inorder to obtain two batches of the desired product with differentpurities.

First batch: 3.79 g; pale brown solid; HPLC: RT=5.65 min, 94%.

Second batch: 320 mg; yellow solid; HPLC: RT=5.65 min, 99%.

The yield of this reaction is 93%.

¹H NMR, dmso-d₆, δ (ppm): 2.68 (s, 3H); 7.66 (t, 1H); 7.72 (t, 1H); 7.83(t, 1H); 7.92 (d, 1H); 8.02-8.15 (m, 4H); 8.28 (dd, 1H); 8.62 (s, 1H);15.62 (broad s, 1H, exch.).

Mass spectrum (ESI+): m/z 384 (MH⁺, 100%).

EXAMPLE 18(7-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 18 was synthesized from the compound 17A (1.0 g, 2.7 mmol)and from iodoethane according to the procedure used for preparing thederivative 1 in order to obtain two batches of the desired product withdifferent purities.

First batch: 716 mg; pale brown solid; HPLC: RT=5.78 min, 89%.

Second batch: 68 mg; yellow solid; HPLC: RT=5.78 min, 99%.

The yield of this reaction is 65%.

¹H NMR, dmso-d₆, δ (ppm): 0.54 (t, 3H); 3.14 (q, 2H); 7.66 (t, 1H); 7.71(t, 1H); 7.82 (t, 1H); 7.92 (d, 1H); 8.00-8.15 (m, 4H); 8.29 (dd, 1H);8.60 (s, 1H); 15.45 (broad s, 1H, exch.).

Mass spectrum (ESI+): m/z 398 (MH⁺, 100%).

EXAMPLE 19 Benzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 1 (86 mg, 0.18 mmol) is dissolved under an inert atmospherein 0.5 mL of dichloromethane and 0.5 mL of pyridine. The reaction mediumis cooled to 0° C. and then benzoyl chloride (33 μl, 0.27 mmol) isadded. The cold bath is removed and the reaction is stirred for 4 hoursat room temperature. As the reaction is incomplete, 16 μl (0.14 mmol) ofbenzoyl chloride are further added and the reaction medium is stirred atroom temperature for a further 20 hours before being concentrated. Theresidue is taken up in ethyl acetate, washed once with water and oncewith an aqueous NaCl saturated solution, dried on sodium sulfate,filtered and concentrated. This second residue is co-evaporated threetimes with toluene in order to remove the remaining pyridine. Thethereby obtained yellow syrup is purified on a column of 12 g ofspherical silica (flow rate 12 mL/min, CH₂Cl₂/heptane gradient from 20to 100% (30 min)), in order to obtain the compound 19 as a yellow foam(38 mg; 44%).

HPLC: RT=5.65 min, 96%

¹H NMR, dmso-d₆, δ (ppm): 3.10 (s, 3H); 7.32 (t, 2H); 7.55-7.30 (m, 6H);7.86 (dd, 2H); 7.90-8.05 (m, 5H); 8.70 (s, 1H).

EXAMPLE 20 Cyclohexanecarboxylic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 1 (86 mg, 0.18 mmol) is st dissolved under an inertatmosphere in 0.5 mL de pyridine. The reaction medium is cooled to 0° C.and then cyclohexanecarbonyl chloride (62 μl, 0.46 mmol) is added. Thecold bath is removed and the reaction is stirred for 18 hours at roomtemperature, and then heated to 60° C. for 8 hours. The reaction mixtureis concentrated and co-evaporated three times with toluene. The therebyobtained residue is purified on a column of 12 g of spherical silica(flow rated 12 mL/min, CH₂Cl₂/heptane gradient from 20 to 100% (20min)), in order to obtain the compound 20 as a yellow foam (65 mg; 28%).

HPLC: RT=5.99 min, 95%

¹H NMR, dmso-d₆, δ (ppm): 0.85-1.00 (m, 6H); 1.38 (de, 2H); 1.49 (de,2H); 2.28 (tt, 1H); 3.06 (s, 3H); 7.66 (t, 2H); 7.75 (t, 1H); 7.83 (t,1H); 7.88 (t, 1H); 7.95-8.15 (m, 5H); 8.66 (s, 1H).

Mass spectrum (ESI+): m/z 493 (MNH₄ ⁺, 100%).

EXAMPLE 21 tertButylcarboxylic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 1 (86 mg, 0.18 mmol) is dissolved under inert atmosphere in0.5 mL of pyridine. The reaction medium is cooled to 0° C. and thentertbutylcarbonyl chloride (57 μl, 0.46 mmol) is added. The cold bath isremoved and the reaction is stirred for 18 hours at room temperature.The reaction medium is concentrated and co-evaporated three times withtoluene. The thereby obtained residue is purified on a column of 12 g ofspherical silica (flow rate 12 mL/min, CH₂Cl₂/heptane gradient from 20to 100% (20 min)), in order to obtain the compound 21 as a yellow foam(47 mg; 53%).

HPLC: RT=5.71 min, 98%

¹H NMR, dmso-d₆, δ (ppm): 0.88 (s, 9H); 3.07 (s, 3H); 7.59 (d, 1H); 7.66(t, 1H); 7.75 (t, 1H); 7.84 (t, 1H); 7.89 (t, 1H); 8.00-8.09 (m, 4H);8.12 (d, 1H); 8.69 (s, 1H).

Mass spectrum (ESI+): m/z 467 (MNH₄ ⁺, 100%).

EXAMPLE 22 4-Methylbenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 22 was synthesized according to the same procedure as forcompound 21 from the compound 1 (86 mg, 0.18 mmol) and from4-methylbenzoyl chloride (62 μl, 0.46 mmol). The product is obtained asa yellow foam (27 mg; 31%).

HPLC: RT=5.82 min, 95%

¹H NMR, dmso-d₆, δ (ppm): 2.28 (s, 3H); 3.10 (s, 3H); 7.11 (d, 2H); 7.54(d, 2H); 7.65 (t, 1H); 7.73 (te, 2H); 7.86 (dd, 2H); 7.95 (d, 1H);7.97-8.05 (m, 4H); 8.69 (s, 1H).

Mass spectrum (ESI+): m/z 501 (MNH₄ ⁺, 100%).

EXAMPLE 23 4-Chlorobenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

4-chlorobenzoic acid (87 mg, 0.55 mmol) is dissolved in 2 mL of tolueneunder an inert atmosphere. Oxalyl chloride (100 μl, 1.1 mmol) is addedat room temperature. The reaction mixture is heated for 2 hours to 80°C., and then concentrated and co-evaporate three times with toluene. Theresidue is put back under an inert atmosphere and cooled to 0° C. Thecompound 1 (86 mg, 0.18 mmol) dissolved under an inert atmosphere in 0.5mL of pyridine and cooled to 0° C. is added. The cold bath is removedand the reaction is stirred for 2 hours at room temperature. Thereaction medium is concentrated and co-evaporated three times withtoluene. The thereby obtained residue is purified on a column of 12 g ofspherical silica (flow rate 12 mL/min, CH₂Cl₂/heptane gradient from 20to 100% (20 min)), in order to obtain the compound 23 as a yellow foam(51 mg; 42%).

HPLC: RT=5.92 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 3.10 (s, 3H); 7.37 (d, 2H); 7.63-7.67 (m, 3H);7.72 (t, 1H); 7.79 (broad s, 1H); 7.86 (broad s, 2H); 7.94 (d, 1H);7.95-8.07 (m, 4H); 8.66 (s, 1H).

Mass spectrum (ESI+): m/z 521 (MNH₄ ⁺, 100%); 523 (MNH₄ ⁺, 37%).

EXAMPLES 24 TO 27

The compounds 24 to 27 were synthesized according to the proceduredescribed for preparing the compound 21, from the compound 15 and fromvarious acid chlorides.

Mass Ex. * R Name of the compounds HPLC Yld. MNH₄ ⁺ 24 tertButyltertButylcarboxylic acid 6- 5.82′ 61% 485 fluoro-2-methyl-3- 98%(naphthalene-2-carbonyl)- 1,1-dioxo-2H- benzo[e][1,2]thiazin-4-yl ester25 Cyclohexane Cyclohexanecarboxylic acid 6- 6.09′ 36% 511fluoro-2-methyl-3- 90% (napthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 26 Phenyl Benzoic acid 6-fluoro-2- 5.73′64% 505 methyl-3-(naphthalene-2- 96% carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 27 4- 4-methylbenzoic acid 6- 5.91′ 56%519 methyl- fluoro-2-methyl-3- 95% phenyl (naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo [e][1,2]thiazin-4-yl ester * ¹H NMR, dmso-d₆, Ex. 24:0.87 (s, 9 H); 3.08 (s, 3 H); 7.32 (d, 1 H); 7.634-7.80 (m, 3 H);7.95-8.15 (m, 5 H); 8.69 (s, 1 H). Ex. 25: 0.80-1.10 (m, 5 H); 1.15-1.55(m, 5 H); 2.39 (te, 1 H); 3.08 (s, 3 H); 7.56 (d, 1 H); 7.65-7.70 (m, 2H); 7.76 (t, 1 H); 7.95-8.15 (m, 5 H); 8.67 (s, 1 H). Ex. 26: 3.12 (s, 3H); 7.29 (t, 2 H); 7.55-7.75 (m, 7 H); 7.94 (d, 1 H); 7.98-8.15 (m, 3H); 8.15 (dd, 1 H); 8.69 (s, 1 H). Ex. 27: 2.28 (s, 3 H); 3.11 (s, 3 H);7.09 (d, 2 H); 7.51 (d, 2 H); 7.60-7.76 (m, 4 H); 7.94 (d, 1 H);7.99-8.08 (m, 3 H); 8.13 (dd, 1 H); 8.69 (s, 1 H).

EXAMPLES 28 TO 31

The compounds 28 to 31 were synthesized according to the proceduredescribed for preparing compound 21, from the compound 16 and variousacid chlorides.

Mass Ex. * R Name of the compounds HPLC Yld MNH₄ ⁺ 28 tertButyltertButylcarboxylic acid 6- 6.00′ 53% 499 fluoro-2-ethyl-3- 98%(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yl ester29 Cyclo- Cyclohexanecarboxylic acid 6- 6.26′ 42% 525 hexanefluoro-2-ethyl-3- 95% (naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yl ester 30 Phenyl Benzoic acid6-fluoro-2- 5.90′ 40% 519 ethyl-3-(naphthalene-2- 99%carbonyl)-1,1-dioxo-2H- benzo[e][1,2]thiazin-4-yl ester 31 4-methyl-4-methylbenzoic acid 6- 6.08′ 59% 533 phenyl fluoro-2-ethyl-3- 95%(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo [e][1,2]thiazin-4-ylester * ¹H NMR, dmso-d₆, Ex. 28: 0.92 (broad s, 12 H); 3.56 (q, 2 H);7.34 (d, 1 H); 7.63-7.80 (m, 3 H); 8.00-8.15 (m, 5 H); 8.68 (s, 1 H).Ex. 29: 0.80-1.10 (m, 8 H); 1.38 (broad s, 3 H); 1.53 (de, 2 H); 2.45(te, 1 H); 3.55 (q, 2 H); 7.56 (d, 1 H); 7.65- 7.70 (m, 2 H); 7.76 (t, 1H); 7.95-8.15 (m, 5 H); 8.67 (s, 1 H). Ex. 30: 0.95 (t, 3 H); 3.58 (q, 2H); 7.35 (t, 2 H); 7.55-7.75 (m, 7 H); 7.96 (d, 1 H); 7.98-8.10 (m, 3H); 8.14 (dd, 1 H); 8.69 (s, 1 H). Ex. 31: 0.95 (t, 3 H); 2.30 (s, 3 H);3.57 (q, 2 H); 7.15 (d, 2 H); 7.60-7.76 (m, 6 H); 7.95 (d, 1 H);7.99-8.08 (m, 3 H); 8.14 (dd, 1 H); 8.68 (s, 1 H).

EXAMPLES 32 AND 33

The compounds 32 and 33 were synthesized according to the proceduredescribed for preparing the compound 23, from 4-chlorobenzoic acid andfrom the compounds 15 and 16, respectively.

Mass Ex. * R Name of the compounds HPLC Yld MNH₄ ⁺ 32 Methyl4-Chlorobenzoic acid 6- 6.00′ 18% 539 fluoro-2-methyl-3- 95%(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-yl ester33 Ethyl 4-Chlorobenzoic acid 6- 6.16′ 19% 553 fluoro-2-ethyl-3- 95%(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-ylester * ¹H NMR, dmso-d₆, Ex. 32: 3.12 (s, 3 H); 7.34 (d, 2 H); 7.55-7.76(m, 6 H); 7.92 (d, 1 H); 7.95-8.05 (m, 3 H); 8.14 (dd, 1 H); 8.65 (s, 1H). Ex. 33: 0.95 (t, 3 H); 3.58 (q, 2 H); 7.40 (d, 2 H); 7.60-7.80 (m, 6H); 7.94 (d, 1 H); 7.00-8.05 (m, 3 H); 8.14 (dd, 1 H); 8.65 (s, 1 H).

EXAMPLE 34

Naphthalen-1-ylcarboxylic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 3 (150 mg, 0.455 mmol) is dissolved under an inertatmosphere in 3 mL of tetrahydrofurane. Sodium hydride (27 mg, 0.68mmol) is added, followed by naphthalen-2-ylcarbonyl chloride (105 μl,0.68 mmol) 30 minutes later. The reaction is stirred for 4 hours at roomtemperature. The reaction medium is neutralized with water and theaqueous phase is extracted twice with ethyl acetate. The organic phasesare combined, dried on magnesium sulfate, filtered and concentrated. Thethereby obtain residue is purified on a column of 12 g of sphericalsilica (flow rate 12 mL/min, gradient of 0 to 45% EtOAc in heptane (20min)). The product is obtained as a yellow solid (134 mg; 61%).

HPLC: RT=6.59 min, 98%

¹H NMR, dmso-d₆, δ (ppm): 2.35 (s, 3H); 3.08 (s, 3H); 7.36 (d, 2H); 7.54(t, 1H); 7.58-7.63 (m, 2H); 7.79-7.87 (m, 3H); 7.92 (d, 2H); 8.00 (d,1H); 8.04-8.07 (m, 2H); 8.27 (d, 1H); 8.50-8.55 (m, 1H).

Mass spectrum (ESI+): m/z 501 (MNH₄ ⁺, 100%).

EXAMPLES 35 TO 45

The compounds 35 to 45 were synthesized according to the proceduredescribed for preparing the compound 34, from the compound 3 or from thecompound 5 and from various acid chlorides.

In the examples 40 to 45, the acid chlorides required for the reactionare prepared in two steps from the corresponding aromatic alcohol. Thepreparation of (naphthalen-2-yloxy)acetyl chloride is given as anexample:

In a two-neck flash provided with a condenser and placed under an inertatmosphere, 2-naphthol (3.0 g, 20 mmol) is dissolved in 95 mL ofmethylethylketone (MEK) in the presence of soda (40 g, 93 mmol), andthen heated to 50° C. for 30 minutes. 2-bromoethanoic acid (5.76 g, 41mmol) dissolved in 23 mL of MEK is added dropwise under hot conditions.The heating is maintained for a further 4 hours. The reaction medium iscooled to room temperature and then filtered. The solid collected byfiltration is taken up in a mixture of ethyl acetate and of 1N HCl inwater. Both phases are separated and the aqueous phase is extracted oncewith ethyl acetate. The organic phases are collected, dried on magnesiumsulfate, filtered and concentrated until the first crystals appear.Heptane is added (about 20% of the remaining volume), and the formedprecipitate is recovered, rinsed with heptane and dried until it hasconstant weight in order to obtain 3.04 g (72%) of(naphthalen-2-yloxy)acetic acid as a white solid.

HPLC: RT=4.10° min, 99%

¹H NMR, dmso-d₆, δ (ppm): 4.80 (s, 2H); 7.20 (dd, 1H); 7.26 (d, 1H);7.35 (td, 1H); 7.45 (td, 1H); 7.79 (d, 1H); 7.80-7.86 (m, 2H); 13.07(broad s, 1H, exch.).

Mass spectrum (ESI+): m/z 203 (MH⁺, 100%).

Mass spectrum (ESI−): m/z 201 (M-H, 100%).

The acid formed earlier (3.04 g, 15 mmol) is partly dissolved under aninert atmosphere and at room temperature in 34 mL of dichloromethane.Oxalyl chloride (1.35 mL, 15.7 mmol) is added followed by 100 μl of DMF.Caution, a violent reaction occurs upon adding DMF. The reaction mixtureis stirred for 1 hour and then concentrated, co-evaporated twice withtoluene and dried until it has constant weight in order to obtain 3.4 g(100%) of (naphthalen-2-yloxy)acetyl chloride as an orangey solid. Thethereby formed acid chloride was used as such in preparing the compounds40 and 41.

Name Mass Ex. * R R′ of the compounds HPLC Yld MNH₄ ⁺ 35 Naphthalen- CH₃Naphthalen-2- 5.89′ 81% 501 2-carbonyl ylcarboxylic 99% acid 2-methyl-3-(4-methylbenzoyl)-1, 1-dioxo-2H-benzo[e] [1,2]thiazin-4-yl ester 36Naphthalen- CN Napthalen-1-yl- 5.59′ 85% 512 1-carbonyl carboxylic acid2- 98% methyl-3-(4-cyano- benzoyl)-1,1-dioxo- 2H-benzo[e][1,2]thiazin-4-yl ester 37 Naphthalen- CN Naphthalen-2-yl- 5.58′ 30% 5122-carbonyl carboxylic acid 2- 93% methyl-3-(4-cyano- benzoyl)-1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yl ester 38 4-chloro CH₃ 4-Chlorobenzoic acid5.82′ 24% 485 benzoyl 2-methyl-3-(4- 96% methylbenzoyl)-1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-yl ester 39 4-chloro CN 4-Chlorobenzoicacid 2- 5.48′ 19% 496 benzoyl methyl-3-(4-cyano- 91% benzoyl)-1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yl ester 40 (Naphthalen- CH₃ (Naphthalene-2-5.87′ 85% 531 2-yloxy) yloxy)acetic acid 2- 98% acetyl methyl-3-(4-methylbenzoyl)-1, 1-dioxo-2H-benzo [e][1,2]thiazin- 4-yl ester 41(Naphthalen- CN (Naphthalene-2- 5.59′ 21% 542 2-yloxy) yloxy)acetic acid2- 98% acetyl methyl-3-(4-cyano- benzoyl)-1,1-dioxo- 2H-benzo[e][1,2]thiazin-4-yl ester 42 (Naphthalen- CH₃ (Naphthalene-1- 5.89′ 60% 5311-yloxy) yloxy)acetic acid 2- 98% acetyl methyl-3-(4- methylbenzoyl)-1,1-dioxo-2H-benzo [e][1,2]thiazin- 4-yl ester 43 (Napthalen- CN(Naphthalene-1- 5.64′ 29% 542 1-yloxy) yloxy)acetic acid 2- 97% acetylmethyl-3-(4-cyano- benzoyl)-1,1-dioxo- 2H-benzo[e][1,2] thiazin-4-ylester 44 (4-chloro CH₃ (4-Chlorophenoxy) 5.76′ 64% 515 phenoxy) aceticacid 2-methyl- 99% acetyl 3-(4-methylbenzoyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 45 (4-chloro CN (4-Chlorophenoxy) 5.50′ 31%526 phenoxy) acetic acid 2-methyl- 90% acetyl 3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo [e][1,2]thiazin-4-yl ester * ¹H NMR, dmso-d₆, Ex. 35:2.34 (s, 3 H); 3.07 (s, 3 H); 7.35 (d, 2 H); 7.65 (t, 1 H); 7.72 (t, 1H); 7.75-7.92 (m, 6 H); 7.95-8.06 (m, 4 H); 8.39 (s, 1 H). Ex. 36: 3.07(s, 3 H); 7.58 (t, 1 H); 7.61-7.68 (m, 2 H); 7.89 (broad s, 3 H); 7.98(d, 2 H); 8.00-8.10 (m, 5 H); 8.31 (d, 1 H); 8.60 (dd, 1 H). Ex. 37:3.08 (s, 3 H); 7.67 (t, 1 H); 7.71-7.79 (m, 2 H); 7.90 (broad s, 3 H);7.99-8.11 (m, 8 H); 8.40 (s, 1 H). Ex. 38: 2.38 (s, 3 H); 3.04 (s, 3 H);7.35 (d, 2 H); 7.58 (d, 2 H); 7.70-7.80 (m, 3 H); 7.83-8.88 (m,4 H);8.02 (broad s, 1 H). Ex. 39: 3.04 (s, 3 H); 7.59 (d, 2 H); 7.83-7.90 (m,3 H); 7.99- 8.07 (m, 5 H). Ex. 40: 2.38 (s, 3 H); 2.97 (s, 3 H); 5.10(s, 2 H); 7.13 (dd, 1 H); 7.20 (d, 1 H); 7.36-7.41 (m, 3 H); 7.48 (t, 1H); 7.67 (d, 1 H); 7.80-7.99 (m, 7 H); 8.00 (broad s, 1 H). Ex. 41: 2.94(s, 3 H); 5.14 (s, 2 H); 7.15 (dd, 1 H); 7.25 (d, 1 H); 7.38 (t, 1 H);7.47 (t, 1 H); 7.69 (d, 1 H); 7.81-7.94 (m, 5 H); 7.99-8.10 (m, 5 H).Ex. 42: 2.38 (s, 3 H); 2.99 (s, 3 H); 5.14 (s, 2 H); 6.70 (d, 1 H); 7.28(t, 1 H); 7.40 (d, 2 H); 7.47-7.55 (m, 3 H); 7.81-7.88 (m, 4 H); 7.92(d, 2 H); 8.00 (d, 1 H); 8.08 (d, 1 H). ). Ex. 43: 2.96 (s, 3 H); 5.20(s, 2 H); 6.82 (d, 1 H); 7.34 (t, 1 H); 7.49- 7.56 (m, 3 H); 7.88-7.56(m, 4 H); 8.00-8.02 (m, 1 H); 8.05-8.11 (m, 5 H). Ex. 44: 2.42 (s, 3 H);2.97 (s, 3 H); 4.98 (s, 2 H); 6.81 (d, 2 H); 7.23 (d, 2 H); 7.42 (d, 2H); 7.81-7.92 (m, 5 H); 7.99 (d, 1 H). Ex. 45: 2.95 (s, 3 H); 5.01 (s, 2H); 6.90 (d, 2 H); 7.28 (d, 2 H); 7.85-8.15 (m, 8 H).

EXAMPLE 46

Acetic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 1 (100 mg, 0.274 mmol) is dissolved under an inertatmosphere in 2 mL of dichloromethane. Triethylamine (230 μl, 1.64 mmol)is added at 0° C., followed by acetyl chloride (78 μl, 1.09 mmol). Thereaction medium is stirred at room temperature for 18 hours and thenconcentrated. The thereby obtained residue is purified on a column of 12g of spherical silica in order to obtain the compound 46 (21 mg; 30%).

HPLC: RT=5.34 min, 97%.

¹H NMR, dmso-d₆, δ (ppm): 1.96 (s, 3H); 3.03 (s, 3H); 7.66 (t, 1H); 7.75(t, 1H); 7.80-7.91 (m, 3H); 7.99-8.08 (m, 4H); 8.12 (d, 1H); 8.67 (s,1H).

Mass spectrum (ESI+): m/z 425 (MNH₄ ⁺, 100%).

EXAMPLES 47 TO 54

The compounds 47 to 54 were synthesized according to the proceduredescribed for preparing the compound 46, from the compound 1 and fromvarious acid chlorides.

Mass Ex. R Name of the compounds HPLC Yld. MNH₄ ⁺ 47 2,4-dichloro-2,4-Dichlorobenzoic acid 2- 6.05′ 47% 555 phenylmethyl-3-(naphthalene-2- 98% carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 48 4-fluoro- 4-Fluorobenzoic acid 2-5.86′ 69% 505 phenyl methyl-3-(naphthalene-2- 98%carbonyl)-1,1-dioxo-2H- benzo[e][1,2]thiazin-4-yl ester 49 Cyclo-Cyclopentanoic acid 2-methyl- 5.99′ 48% 479 pentyl3-(naphthalene-2-carbonyl)- 91% 1,1-dioxo-2H-benzo[e][1,2] thiazin-4-ylester 50 Furan-2-yl 2-Furanoic acid 2-methyl-3- 5.33′ 68% 477(napthalene-2-carbonyl)- 97% 1,1-dioxo-2H-benzo[e][1,2] thiazin-4-ylester 51 Thiophen- Thiophen-2-carboxylic acid 2- 5.68′ 61% 493 2-ylmethyl-3-(naphthalene-2- 99% carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 52 3-chloro- 3-Chlorobenzoic acid 2-5.87′ 45% 521 phenyl methyl-3-(naphthalene-2- 98%carbonyl)-1,1-dioxo-2H- benzo[e][1,2]thiazin-4-yl ester 53 2-chloro-2-Chlorobenzoic acid 2- 5.74′ 63% 521 phenyl methyl-3-(naphthalene-2-96% carbonyl)-1,1-dioxo-2H- benzo[e][1,2]thiazin-4-yl ester 54 Phenoxy-Phenoxyacetic acid 2-methyl- 5.63′ 71% 517 methyl3-(naphthalene-2-ylcarbonyl)- 97% 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester * ¹H NMR, dmso-d₆, Ex. 47: 3.11 (s, 3 H); 7.29 (d, 1H); 7.58 (d, 1 H); 7.62-7.68 (m, 2 H); 7.72 (t, 1 H); 7.82-7.92 (m, 3H); 7.95-8.09 (m, 5 H); 8.66 (s, 1 H). Ex. 48: 3.10 (s, 3 H); 7.15 (t, 2H); 7.63-8.08 (m, 12 H); 8.67 (s, 1 H). Ex. 49: 1.20-1.31 (m, 6 H);1.50-1.58 (m, 2 H); 2.75 (quintet, 1 H); 3.07 (s, 3 H); 7.64-7.70 (m, 2H); 7.74 (t, 1 H); 7.84 (t, 1 H); 7.89 (t, 1 H); 7.99-8.08 (m, 4 H);8.12 (d, 1 H); 8.67 (s, 1 H). Ex. 50: 3.08 (s, 3 H); 6.60 (d, 1 H); 7.19(d, 1 H); 7.65 (t, 1 H); 7.72-7.77 (m, 2 H); 7.88 (broad s, 2 H);7.95-8.08 (m, 6 H); 8.69 (s, 1 H). Ex. 51: 3.09 (s, 3 H); 7.09 (dd, 1H); 7.62-8.04 (m, 12 H); 8.20 (s, 1 H). Ex. 52: 3.12 (s, 3 H); 7.6 (t, 1H); 7.41 (s, 1 H); 7.60-7.67 (m, 3 H); 7.72 (t, 1 H); 7.82-8.08 (m, 8H); 8.69 (s, 1 H). Ex. 53: 3.11 (s, 3 H); 7.20 (t, 1 H); 7.49-7.57 (m, 3H); 7.65 (t, 1 H); 7.73 (t, 1 H); 7.80 (d, 1 H); 7.85-7.93 (m, 2 H);7.98-8.09 (m, 5 H); 8.71 (s, 1 H). Ex. 51: (t, 2 H); 7.65 (t, 1 H); 7.76(t, 1 H); 7.83-7.92 (m, 3 H); 8.03-8.09 (m, 4 H); 8.14 (d, 1 H); 8.71(s, 1 H).

EXAMPLE 55

(4-Methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 1 (159 mg, 0.435 mmol) is dissolved under an inertatmosphere in 2 mL of DMF. Sodium hydride (26 mg, 0.65 mmol) is added,followed by methane iodide (30 μl, 0.48 mmol) 30 minutes later. Thereaction is stirred for 2 hours at room temperature, and then for 26hours at 60° C. At this stage, the reaction is still incomplete. Cesiumcarbonate (213 mg, 0.65 mmol) and methane iodide (150 μl, 2.1 mmol) areadded. The reaction medium is stirred for 24 hours at room temperatureand then neutralized with water, and the aqueous phase is extractedtwice with ethyl acetate. The organic phases are combined, dried onmagnesium sulfate, filtered and concentrated. The thereby obtainedresidue is purified on a column of 12 g of spherical silica (flow rate12 mL/min, gradient of 20 to 60% dichloromethane in heptane), in orderto obtain the compound 55 as a yellow foam (70 mg; 38%).

HPLC: RT=5.27 min, 90%

Mass spectrum (ESI+): m/z 380 (MH⁺, 100%).

EXAMPLES 56 TO 58

The compounds 56 to 58 were prepared according to the followingprocedure:

The compound 1 (150 mg, 0.42 mmol) is dissolved under an inertatmosphere in 0.3 mL of DMF. Cesium carbonate (201 mg, 0.61 mmol) andthe require alkyl iodide (4 mmol) are added. The reaction medium isstirred for 18 hours at room temperature, for 4 hours at 50° C. and thenneutralized with water, and the aqueous phase is extracted twice withethyl acetate. The organic phases are combined, dried on magnesiumsulfate, filtered and concentrated. The thereby obtained residues arepurified on columns of 12 g of spherical silica (flow rate 12 mL/min,gradient of 20 to 60% dichloromethane in heptane), in order to obtainthe desired products.

Mass Ex. R Name of the compounds HPLC Yld. MH⁺ 56 Ethyl(4-ethoxy-2-methyl-1,1-dioxo-2H- 5.43′ 66% 394 benzo[e][1,2]thiazin-3-99% yl) (naphthalen-2-yl)methanone 57 n-(4-propyloxy-2-methyl-1,1-dioxo- 5.61′ 65% 408 Propyl 2H-benzo[e][1,2]thiazin-3- 99% yl) (naphthalen-2-yl)methanone 58 n-Butyl(4-butyloxy-2-methyl-1,1-dioxo-2H- benzo[e][1,2] thiazin-3- 5.81′ 24%422 yl) (naphthalen-2-yl)methanone 97% * ¹H NMR, dmso-d₆, Ex. 56: 0.87(t, 3H): 2.98 (s, 3H); 3.74 (q, 2H); 7.64 (t, 1H); 7.72 (t, 1H);7.80-7.93 (m, 3H); 7.95-8.15 (m, 5H); 8.67 (s, 1H). Ex. 57: 0.49 (t,3H): 1.28 (sextet, 2H); 2.97 (s, 3H); 3.63 (t, 2H); 7.64 (t, 1H); 7.72(t, 1H); 7.80-7.93 (m, 3H); 7.95-8.15 (m, 5H); 8.68 (s, 1H). Ex. 58:0.50 (t, 3H): 0.89 (sextet, 2H); 1.23 (quintet, 2H); 2.97 (s, 3H); 3.66(t, 2H); 7.64 (t, 1H); 7.72 (t, 1H); 7.80-7.93 (m, 3H); 7.95-8.15 (m,5H); 8.67 (s, 1H).

EXAMPLE 59(4-(2-Chloroethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanone

The compound 3 (100 mg, 0.3 mmol) is dissolved in 3 mL of THF, under aninert atmosphere and in the presence of 2-chloroethanol (100 μl, 1.5mmol). The reaction mixture is cooled to 0° C., and thentriphenylphosphine (318 mg, 1.2 mmol) anddiethyldiazene-1,2-dicarboxylate (DEAD, 211 mg, 1.2 mmol) aresuccessively added dropwise. Stirring is continued for 20 hours at roomtemperature, and then the reaction is neutralized with an aqueoussolution saturated with ammonium chloride. This aqueous phase isextracted twice with ethyl acetate. The organic phases are combined,dried on magnesium sulfate, filtered and concentrated. The therebyobtained residue is purified on a column of 35 g of silica (flow rate 20mL/min, gradient of 0 to 100% ethyl acetate in heptane), in order toobtain the compound 59 (70 mg; 58%).

HPLC: RT=5.28 min, 99%

¹H NMR, dmso-d₆, δ (ppm): 2.41 (s, 3H); 2.91 (s, 3H); 3.57 (t, 2H); 3.92(t, 2H); 7.40 (d, 2H,); 7.75-7.98 (m, 6H).

Mass spectrum (ESI+): m/z 392 (MH⁺, 100%); 394 (MH⁺, 42%).

EXAMPLE 60(4-[2-(Naphthalen-2-yloxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanone

The compound 59 (70 mg, 0.17 mmol) is dissolved in 2 mL of DMF, under aninert atmosphere and in the presence of potassium carbonate (64 mg, 0.53mmol), potassium iodide (31 mg, 0.19 mmol) and 2-naphthol (38 mg, 0.27mmol). The reaction medium is heated to 65° C., for 22 hours, and thenneutralized with water and extracted twice with ethyl acetate. Theorganic phases are combined, dried on magnesium sulfate, filtered andconcentrated. The thereby obtained residue is purified bysemi-preparative HPLC on a Waters Sunfire column (19×100 mm, 5 μm), witha flow of 20 mL/min and a 15 minute gradient of 10 to 100% acetonitrilein water (0.1% TFA buffer), in order to obtain the compound 60 (30 mg;29%).

HPLC: RT=5.95 min, 99%

¹H NMR, dmso-d₆, δ (ppm) 2.26 (s, 3H); 2.90 (s, 3H); 4.03 (d, 2H); 4.10(d, 2H); 6.92 (dd, 1H); 7.06 (d, 1H); 7.24 (d, 2H); 7.33 (t, 1H); 7.44(t, 1H); 7.70-7.90 (m, 7H); 7.94-7.98 (m, 2H).

Mass spectrum (ESI+): m/z 500 (MH⁺, 100%).

EXAMPLE 61(4-(2-Phenoxy-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 1 (100 mg, 0.274 mmol) is dissolved in 0.5 mL of DMF inpresence of potassium carbonate (90 mg, 0.55 mmol) and 2-phenoxyethylbromide (110 mg, 0.55 mmol). The reaction medium is heated in a sealedtube, to 80° C. for 16 hours. The medium is taken up in ethyl acetateand then washed with water and with a saturated NaCl solution. Theorganic phases are combined, dried on sodium sulfate, filtered andconcentrated. The thereby obtained residue is purified on a column of 12g of silica (flow rate 20 mL/min, gradient of 0 to 10% dichloromethanein heptane), in order to obtain the compound 61 as a yellow syrup (45mg; 34%).

HPLC: RT=5.88 min, 98%

¹H NMR, dmso-d₆, δ (ppm) 2.97 (s, 3H); 3.85-3.87 (m, 2H); 4.01-4.05 (m,2H); 6.59 (d, 2H); 6.82 (t, 1H); 7.11 (t, 2H); 7.62 (t, 1H); 7.71 (t,1H); 7.83 (t, 1H); 7.88 (t, 1H); 7.91-8.04 (m, 6H); 8.62 (s, 1H).

Mass spectrum (ESI+): m/z 486 (MH⁺, 100%).

EXAMPLE 62 Methyl2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetate

The compound 62 was synthesized according to the same procedure as thecompound 59 from the compound 3 (300 mg, 0.91 mmol) and from methylglycolate (350 μl, 4.5 mmol) in order to obtain 300 mg (79%) of thedesired product as a yellow syrup.

HPLC: RT=4.97 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 2.42 (s, 3H); 2.88 (s, 3H); 3.47 (s, 3H); 4.42(s, 2H); 7.40 (d, 2H,); 7.75-7.98 (m, 6H).

Mass spectrum (ESI+): m/z 402 (MH⁺, 100%); 419 (MNH₄ ⁺, 42%).

EXAMPLE 63(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)aceticacid

The compound 62 (75 mg, 0.18 mmol) is dissolved in 1 mL of THF, andlithium hydroxide (1M/H₂O, 0.37 mmol) is added. The reaction medium isstirred at room temperature for 2 hours, and then diluted in water andextracted twice with dichloromethane. The organic phases are combined,dried on magnesium sulfate, filtered and concentrated in order to obtain22 mg of the desired product (HPLC: RT=4.55 min, 97%). The yield of thisoperation is 30%.

¹H NMR, dmso-d₆, δ (ppm) 2.41 (s, 3H); 2.88 (s, 3H); 4.28 (s, 2H); 7.39(d, 2H); 7.81 (t, 1H); 7.85-7.95 (m, 5H); 12.96 (se, 1H, exch.).

Mass spectrum (ESI+): m/z 388 (MH⁺, 100%); 405 (MNH₄ ⁺, 54%

EXAMPLES 64 TO 66

The compound 63 (110 mg, 0.28 mmol) is dissolved in 3 mL of DMF.Different amines (0.23 mmol), DIEA (82 μl, 0.472 mmol), HOOBT (35 mg,0.26 mmol) EDCI (50 mg, 0.26 mmol) are added. The reaction medium isstirred for 18 hours at room temperature. The medium is taken up indichloromethane and then washed with 1N soda, water, and a saturatedNaCl solution. The organic phases are combined, dried on magnesiumsulfate, filtered and concentrated. The thereby obtained residues arepurified on columns of 12 g of spherical silica (flow rate 12 mL/min, 0to 50% AcOEt in heptane), in order to obtain the desired products.

Mass Ex. R1R2N Name of the compounds HPLC Yld MNH₄ ⁺ 64 Naphthalen-2-(2-methyl-3-(4-methylbenzoyl)- 5.45′ 40% 530 1-yl 1,1-dioxo-2H- 95%benzo[e][1,2]thiazin-4-yloxy)-N- (naphthalen-1-yl)acetamide 65Adamantan- 2-(2-methyl-3-(4-methylbenzoyl)- 5.90′ 72% 538 1-yl1,1-dioxo-2H- 99% benzo[e][1,2]thiazin-4-yloxy)-N-(adamantan-1-yl)acetamide 66 Adamantan- 2-(2-methyl-3-(4-methylbenzoyl)-5.83′ 85% 538 2-yl 1,1-dioxo-2H- 99% benzo[e][1,2]thiazin-4-yloxy)-N-(adamantan-2-yl)acetamide * ¹H NMR, dmso-d₆, Ex. 64: 2.33 (s, 3 H); 2.93(s, 3 H); 4.55 (s, 2 H); 7.35 (d, 2 H); 7.43-7.55 (m, 4 H); 7.76 (d, 1H); 7.82-7.85 (m, 2 H); 7.91-7.99 (m, 5 H); 8.12 (d, 1 H); 7.76 (s, 1 H,exch). 65: 1.51-1.59 (m, 6 H); 1.71 (s, 6 H); 1.94 (s, 3 H); 2.41 (s, 3H); 2.88 (s, 3 H); 4.05 (s, 2 H); 6.78 (s, 1 H); 7.42 (s, 2 H); 7.81 (t,1 H); 7.87-7.95 (m, 4 H); 7.99 (d, 1 H). 66: 1.39-1.41 (m, 2 H);1.64-1.77 (m, 12 H); 2.41 (s, 3 H); 2.88 (s, 3 H); 3.65-3.75 (m, 1 H);4.21 (s, 2 H); 7.39 (d, 3 H); 7.81 (t, 1 H); 7.87-7.95 (m, 4 H); 8.0 (d,1 H).

EXAMPLE 67

Methyl2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetate

The compound 1 (1.0 g, 2.74 mmol) is dissolved in 2 mL of DMF in thepresence of potassium carbonate (682 mg, 4.1 mmol) and methylbromoacetate (1.26 mL, 13.68 mmol). The reaction medium is stirred atroom temperature for 5 hours and then the same amount of methylbromoacetate is added again. After one night at room temperature, themixture is taken up in ethyl acetate and then washed with water and witha saturated NaCl solution. The organic phases are combined, dried onsodium sulfate, filtered and concentrated. The thereby obtained residueis purified on a column of 90 g of silica (flow rate 32 mL/min, gradientof 40 to 100% dichloromethane in heptane), in order to obtain thecompound 67 as a yellow syrup (486 mg; 41%).

HPLC: RT=5.23 min, 86%

¹H NMR, dmso-d₆, δ (ppm) 2.95 (s, 3H); 3.39 (s, 3H); 4.45 (s, 2H); 7.64(t, 1H); 7.72 (t, 1H); 7.81-7.89 (m, 1H); 7.93 (d, 2H); 7.97 (d, 1H);7.99-8.11 (m, 4H); 8.66 (s, 1H).

Mass spectrum (ESI+): m/z 438 (MH⁺, 100%).

EXAMPLE 682-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)aceticacid

The compound 67 (480 mg, 1.1 mmol) is dissolved in THF/water 5:1 mixture(6 mL) and then treated with LiOH (103 mg, 4.39 mmol) at roomtemperature for 15 minutes. The medium is taken up in ethyl acetate andthen washed with 1N HCl, water and with a saturated NaCl solution. Theorganic phases are combined, dried on sodium sulfate, filtered andconcentrated. The thereby obtained residue is purified on a column of 30g of silica (dichloromethane/methanol/acetic acid 95/4.5/0 eluent), inorder to obtain the compound 68 as a yellow foam (321 mg; 69%).

HPLC: RT=4.86 min, 99%

¹H NMR, dmso-d₆, δ (ppm) 2.93 (s, 3H); 4.29 (s, 2H); 7.64 (t, 1H); 7.72(t, 1H); 7.83 (t, 1H); 7.89-8.09 (m, 7H); 8.66 (s, 1H).

Mass spectrum (ESI+): m/z 424 (MH⁺, 100%).

EXAMPLES 69 TO 71

The compounds 69 to 71 were prepared according to the followingprocedure:

The compound 1 (100 mg, 0.23 mmol) is dissolved in 1.5 mL ofdichloromethane. Different amines (0.23 mmol), DIEA (82 μl, 0.472 mmol),HOOBT (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol) are added. Thereaction mixture is stirred for 24 hours at room temperature and thenamine in excess is added (0.07 mmol) and the medium is stirred for afurther 5 hours. The medium is taken up in dichloromethane and washedwith 1N soda, water and with a saturated NaCl solution. The organicphases are combined, dried on sodium sulfate, filtered and concentrated.The thereby obtained residues are purified on columns of 12 g ofspherical silica (flow rate 12 mL/min, 1% of a methanol/ammonia 9:1mixture in dichloromethane), in order to obtain the desired products.

Mass Ex. NR₁R₂ Name of the compounds HPLC Yld MH⁺ 69

2-[2-Methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1- piperidin-1-yl-ethanone 5.26′98% 49% 491 70

2-[2-Methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazin-1-yl)-ethanone 3.93′ 98% 47% 506 71

1-(4-Benzyl-piperazin-1-yl)-2-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethanone 4.28′ 98% 20% 582 *¹H NMR,dmso-d₆, Ex. 69: 1.08-1.31 (m, 6 H): 2.87 (t, 2 H); 2.95 (s, 3 H); 3.04(t, 2 H); 4.41 (s, 2 H); 7.64 (t, 1 H); 7.72 (t, 1 H); 7.84 (m, 1 H);7.92 (d, 2 H); 7.97-8.10 (m, 5 H); 8.65 (s, 1 H). Ex. 70: 1.85 (t, 2 H):1.92 (t, 2 H); 1.95 (s, 3 H); 2.94 (broad s, 5 H); 3.04 (broad s, 2 H);4.44 (s, 2 H); 7.64 (t, 1 H); 7.72 (t, 1 H); 7.84 (m, 1 H); 7.92 (m, 2H); 7.97-8.10 (m, 5 H); 8.65 (s, 1 H). Ex. 71: 1.88 (broad s, 2 H); 1.96(broad s, 2 H); 2.92 (m, 5 H); 3.08 (broad s, 2 H); 3.22 (s, 2 H); 4.42(s, 2 H); 7.16 (d, 2 H); 7.21-7.31 (m, 3 H); 7.63 (t, 1 H); 7.72 (t, 1H); 7.82 (m, 1 H); 7.78 (m, 2 H); 7.97-8.09 (m, 5 H); 8.65 (s, 1 H).

EXAMPLES 72 TO 74

The compounds 72 to 74 were synthesized according to the proceduredescribed for preparing the compound 46, from the compound 1 and fromvarious acid chlorides.

Mass Ex. R Name of the compounds HPLC Yld. MNH₄ ⁺ 72 4-(4-Chloro-phenoxy)-acetic acid 2- 6.02′ 77% 551 chloro-methyl-3-(naphthalene-2- 94% phenyl- carbonyl)-1,1-dioxo-2H- oxy-benzo[e][1,2]thiazin-4-yl ester acetyl 73 Naphthalen-(Naphthalen-1-yloxy)-acetic acid 6.16′ 84% 567 1-yloxy-2-methyl-3-(naphthalene-2- 98% acetyl carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 74 Naphthalen- (Naphthalen-2-yloxy)-acetic acid6.11′ 83% 567 2-yloxy- 2-methyl-3-(naphthalene-2- 96% acetylcarbonyl)-1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-yl ester *¹H NMR,dmso-d₆, Ex. 72: 3.04 (s, 3 H); 4.94 (s, 2 H); 6.67 (d, 2 H); 7.07 (d, 2H); 7.64 (t, 1 H); 7.72 (t, 1 H); 7.84-7.93 (m, 3 H); 8.02 (m, 3 H);8.08 (d, 1 H); 8.14 (d, 1 H); 8.69 (s, 1 H). Ex. 73: 3.05 (s, 3 H); 5.10(s, 2 H); 6.59 (d, 1 H); 7.12 (t, 1 H); 7.38-7.41 (m, 2 H); 7.49 (t, 1H); 7.66 (t, 1 H); 7.75 (t, 1 H); 7.81-7.90 (m, 4 H); 7.98 (d, 1 H);8.02-8.08 (m, 4 H); 8.13 (d, 1 H); 8.72 (s, 1 H). Ex. 74: 3.02 (s, 3 H);5.07 (s, 2 H); 7.01 (dd, 1 H); 7.12 (d, 1 H); 7.32-7.41 (m, 2 H); 7.57(d, 1 H); 7.63 (t, 1 H); 7.70-7.79 (m, 3 H); 7.85-7.94 (m, 3 H);8.02-8.12 (m, 5 H); 8.71 (s, 1 H).

EXAMPLES 75 AND 76

The compounds 75 and 76 were synthesized according to the proceduredescribed for preparing the compound 60, from the compound 59 andvarious alcohols.

Mass Ex. R Name of the compounds HPLC Yld. MH⁺ 75 Naphthalen-(4-[2-(naphthalen-1- 6.00′ 38% 500 1-yl yloxy)ethoxy]-2-methyl- 97%1,1-dioxo-2H-benzo[e][1,2] thiazin-3-yl)(p-tolyl) methanone 76 4-(4-[2-(4-chlorophenyl- 5.87′ 48% 484 Chlorophenyl oxy)ethoxy]-2-methyl-98% 1,1-dioxo-2H-benzo[e] [1,2]thiazin-3-yl)(p- tolyl) methanone *¹HNMR, dmso-d₆, Ex. 75: 2.31 (s, 3 H); 2.90 (s, 3 H); 4.10-4.20 (m, 4 H);6.75 (d, 1 H); 7.21 (d, 2 H); 7.33 (t, 1 H); 7.40-7.44 (m, 2 H); 7.51(t, 1 H); 7.78-7.85 (m, 6 H); 7.97 (t, 2 H). Ex. 76: 2.37 (s, 3 H); 2.89(s, 3 H); 3.85-3.95 (m, 2 H); 4.00-4.05 (m, 2 H); 6.69 (d, 2 H); 7.23(d, 2 H); 7.29 (d, 2 H); 7.78-7.96 (m, 6 H).

EXAMPLES 77 AND 78

The compounds 77 and 78 were synthesized according to the proceduredescribed for preparing the compound 34, from the compound 3 and fromacetyl chloride and propanoyl chloride respectively.

Ex. R Name of the compounds HPLC Yld. MNH₄ ⁺ 77 Methyl Acetic acid2-methyl-3-(4- 5.05′ 81% 389 methylbenzoyl)-1,1-dioxo-2H- 99%benzo[e][1,2]thiazin-4-yl ester 78 Ethyl Propanoic acid 2-methyl-3-(4-5.25′ 88% 403 methylbenzoyl)-1,1-dioxo-2H- 99% benzo[e][1,2]thiazin-4-ylester *¹H NMR, dmso-d₆, Ex. 77: 2.04 (s, 3 H); 2.42 (s, 3 H); 2.98 (s, 3H); 7.42 (d, 2 H); 7.76-7.90 (m, 5 H); 7.98 (d, 1 H). Ex. 78: 0.86 (t, 3H); 2.33 (q, 2 H); 2.42 (s, 3 H); 2.99 (s, 3 H); 7.41 (d, 2 H); 7.73 (d,1 H); 7.79-7.89 (m, 4 H); 7.98 (d, 1 H).

EXAMPLES 79 AND 80

The compounds 79 et 80 were synthesized according to the proceduredescribed for preparing the compound 59, from the compound 3 and frommethanol and ethanol respectively.

Mass Ex. R Name of the compounds HPLC Yld. MH⁺ 79 Methyl(4-methyloxy-2-methyl- 5.13′ 58% 344 1,1-dioxo-benzo[e][1,2] 98%thiazin-3-yl)(p- tolyl)methanone 80 Ethyl (4-ethyloxy-2-methyl- 5.29′63% 358 1,1-dioxo-2H-benzo 99% [e][1,2]thiazin-3-yl) (p-tolyl)methanone*¹H NMR, dmso-d₆, Ex. 79: 2.42 (s, 3 H); 2.91 (s, 3 H); 3.50 (s, 3 H);7.41 (d, 2 H); 7.78-7.95 (m, 6 H). Ex. 80: 0.93 (t, 3 H); 2.41 (s, 3 H);2.90 (s, 3 H); 3.73 (q, 2 H); 7.40 (d, 2 H); 7.78-7.94 (m, 6 H).

EXAMPLE 81[4-(2-Bromo-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]-naphthalen-2-yl-methanone

The compound 1 (150 mg, 0.41 mmol) is dissolved in methylethylketone (3mL) and then treated with dibromoethane (71 μl, 0.82 mmol) in thepresence of K₂CO₃ (170 mg, 1.02 mmol). The reaction is heated withmicrowave energy in a sealed tube at 130° C. for 4 h 30 min. The mediumis taken up in ethyl acetate and then washed with water and with asaturated NaCl solution. The organic phases are combined, dried onsodium sulfate, filtered and concentrated. The thereby obtained residue(brown syrup, 197 mg) is directly engaged into the next reaction.

EXAMPLE 82{4-[2-(4-Chloro-phenoxy)-ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl}-naphthalen-2-yl-methanone

The compound 81 (197 mg, 0.41 mmol) is dissolved in methylethylketone(1.5 mL) and then treated with 4-chlorophenol (107 μl, 0.82 mmol) in thepresence of K₂CO₃ (173 mg, 1.04 mmol). The reaction is heated withmicrowave energy in a sealed tube at 130° C. for 2 hours. The medium istaken up in ethyl acetate and then washed with water and with asaturated NaCl solution. The organic phases are combined, dried onsodium sulfate, filtered and concentrated. The thereby obtained residueis purified on a column of 12 g of silica (flow rate 12 mL/min, gradientof 10 to 100% dichloromethane in heptane), in order to obtain thecompound 82 as a yellow syrup (21 mg; 14%).

HPLC: RT=6.10 min, 89%

¹H NMR, dmso-d₆, δ (ppm) 2.96 (s, 3H); 3.85 (m, 2H); 3.97 (m, 2H); 6.57(d, 2H); 7.08 (d, 2H); 7.61 (t, 1H); 7.70 (t, 1H); 7.83 (t, 1H);7.89-8.02 (m, 7H); 8.60 (s, 1H).

Mass spectrum (ESI+): m/z 520 (MH⁺, 66%).

EXAMPLE 83

Carbonic acid ethyl ester1-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethylester

The compound 1 (100 mg, 0.27 mmol) is dissolved in DMF (1 mL) and thentreated with ethyl 2-chloropropanoate (110 μl, 0.82 mmol) in thepresence of K₂CO₃ (91 mg, 0.55 mmol). The reaction is heated in a sealedto 60° C. overnight and then the same amount of ethyl 2-chloropropanoateis added and the reaction is stirred for a further 24 hours. The mediumis taken up into ethyl acetate and then washed with water and with asaturated NaCl solution. The organic phases are combined, dried onsodium sulfate, filtered and concentrated. The thereby obtained residueis purified on a column of 12 g of silica (flow rate 12 mL/min, gradientof 25 to 80% dichloromethane in heptane), in order to obtain thecompound 83 as a yellow syrup (100 mg; 76%).

HPLC: RT=5.55 min, 97%

¹H NMR, dmso-d₆, δ (ppm) 0.94 (t, 3H); 1.25 (d, 3H); 2.94 (s, 3H);3.80-3.93 (m, 2H); 5.99 (q, 1H); 7.65 (t, 1H); 7.73 (t, 1H); 7.85 (m,1H); 7.90 (d, 2H); 7.97 (d, 1H); 8.01-8.11 (m, 4H); 8.69 (s, 1H).

Mass spectrum (ESI+): m/z 504 (MNa⁺, 100%).

EXAMPLE 84[2-Methyl-1,1-dioxo-4-(2-piperidin-1-yl-ethoxy)-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl]-naphthalen-2-yl-methanone

The compound 1 (100 mg, 0.27 mmol) is dissolved in methylethylketone(0.5 mL) and then treated with 1-(2-chloroethyl)piperidine (252 mg, 1.37mmol) in the presence of K₂CO₃ (159 mg, 0.96 mmol). The reaction isheated to 80° C. overnight. The medium is further taken up with ethylacetate and then washed with water and with a saturated NaCl solution.The organic phases are combined, dried on sodium sulfate, filtered andconcentrated. The thereby obtained residue is purified on a 12 g silicacolumn (flow rate 12 mL/min, dichloromethane/MeOH/NH₄OH 99/09/01), inorder to obtain the compound 84 as a yellow syrup (50 mg; 43%).

HPLC: RT=4.17 min, 92%

¹H NMR, dmso-d₆, δ (ppm): 1.21 (broad s, 6H); 1.99 (broad s, 4H); 2.19(t, 2H); 2.98 (s, 3H); 3.72 (t, 2H); 7.64 (t, 1H); 7.72 (t, 1H); 7.83(t, 1H); 7.90 (t, 1H); 7.97 (d, 1H); 8.01-8.11 (m, 5H); 8.66 (s, 1H).

Mass spectrum (ESI+): m/z 477 (MH⁺, 100%).

EXAMPLES 85 TO 96

The compounds 85 to 96 were synthesized according to the followingprocedure:

The compounds 13, 15, or 17 (100 mg) are dissolved under an inertatmosphere in 2 mL of dichloromethane in the presence or triethylamine(6 eq.) and then treated with various acid chlorides (4 eq.) at 0° C.The reaction mixtures are stirred for 2 hours at 0° C. and then at roomtemperature for 20 hours. The media are taken up in ethyl acetate andthen washed with water and with a saturated NaCl solution. The organicphases are combined, dried on sodium sulfate, filtered and concentrated.The thereby obtained residues are purified on a column of 12 g of silica(flow rate 12 mL/min, gradient of 0 to 20% ethyl acetate in heptane), inorder to obtain the expected compounds.

Mass MH⁺/ Ex. R1 R2 Name of the compounds HPLC Yld. MNa⁺ 85 4- 5-4-Chloro-benzoic acid 5- 6.43′ 29% 555 chloro- Cl chloro-2-methyl-3- 96%phenyl (naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo [e][1,2]thiazin-4-ylester 86 Cyclo- 5- Cyclohexanecarboxylic 6.50′ 26% 527 hexyl Cl acid5-chloro-2-methyl-3- 98% (naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 87 Phenyl 5- Benzoic acid 5-chloro-2- 6.11′65% 521 Cl methyl-3-(naphthalene- 92% 2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4- yl ester 88 4- 6-F 4-Chloro-benzoic acid 6.30′40% 539 Chloro- 6-fluoro-2-methyl- 99% phenyl3-(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-ylester 89 Cyclo- 6-F Cyclohexanecarboxylic 6.30′ 55% 511 hexyl acid6-fluoro-2-methyl-3- 97% (naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 90 Phenyl 6-F Benzoic acid 6-fluoro-2- 5.90′ 50%505 methyl-3-(naphthalene-2- 94% carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4- yl ester 91 4- 7-F 4-Chloro-benzoic acid 6.20′60% 539 chloro- 7-fluoro-2-methyl-3- 98% phenyl(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-yl ester92 Cyclo- 7-F Cyclohexanecarboxylic 6.37′ 19% 511 hexyl acid7-fluoro-2-methyl-3- 98% (naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 93 Phenyl 7-F Benzoic acid 7-fluoro- 5.91′69% 505 2-methyl-3- 93% (naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 94 Methyl 7-F Acetic acid 7-fluoro-2- 5.46′ 62%448 methyl-3-(naphthalene- 97% 2-carbonyl)-1,1- dioxo-2H-benzo[e][1,2]thiazin-4-yl ester 95 Phenoxy- 7-F Phenoxy-acetic acid 5.89′ 50% 540methyl 7-fluoro-2-methyl-3- 92% (naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e] [1,2]thiazin-4-yl ester 96 4-Cl- 7-F(4-Chloro-phenoxy)-acetic 6.10′ 18% 574 phenoxy- acid7-fluoro-2-methyl-3- 93% methyl (naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo [e][1,2]thiazin-4-yl ester

EXAMPLES 97 TO 104

The compounds 97 to 104 were synthesized according to the procedure usedfor preparing examples 56 to 58 from the compound 13, 15, or 17 and fromcorresponding alkyl iodides or sulfates.

Mass MH⁺/ Ex. R1 R2 Name of the compounds HPLC Yld. MNH4⁺  97 Ethyl 5-Cl(5-Chloro-4-ethoxy-2- 5.61′ 11% 428 methyl-1,1-dioxo-2H- 97%benzo[e][1,2]thiazin- 3-yl)-naphthalen- 2-yl-methanone  98 Propyl 5-Cl(5-Chloro-4-propoxy-2- 6.02′ 44% 442 methyl-1,1-dioxo-2H- 96%benzo[e][1,2]thiazin- 3-yl)-naphthalen-2- yl-methanone  99 Methyl 6-F(6-Fluoro-4-methoxy-2- 5.65′ 34% 398 methyl-1,1-dioxo-2H- 93%benzo[e][1,2]thiazin- 3-yl)-naphthalen-2- yl-methanone 100 Ethyl 6-F(6-Fluoro-4-ethoxy-2- 5.72′ 52% 429 methyl-1,1-dioxo-2H- 97%benzo[e][1,2]thiazin- 3-yl)-naphthalen-2- yl-methanone 101 Propyl 6-F(6-Fluoro-4-propoxy-2- 5.92′ 56% 426 methyl-1,1-dioxo-2H- 97%benzo[e][1,2]thiazin- 3-yl)-naphthalen-2- yl-methanone 102 Methyl 7-F(7-Fluoro-4-methoxy-2- 5.56′ 20% 398 methyl-1,1-dioxo-2H- 97%benzo[e][1,2]thiazin- 3-yl)-naphthalen-2- yl-methanone 103 Ethyl 7-F(7-Fluoro-4-ethoxy-2- 5.77′ 47% 412 methyl-1,1-dioxo-2H- 95%benzo[e][1,2]thiazin- 3-yl)-naphthalen-2- yl-methanone 104 Propyl 7-F(7-Fluoro-4-propoxy-2- 5.90′ 52% 426 methyl-1,1-dioxo-2H- 98%benzo[e][1,2]thiazin- 3-yl)-naphthalen- 2-yl-methanone

EXAMPLE 105[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-aceticacid methyl ester

The compound 105 was synthesized according to the procedure used forpreparing example 67 from the compound 17 (1 g, 2.61 mmol). The productis obtained as a yellow syrup (810 mg; 68%).

HPLC: RT=5.37 min, 95%

¹H NMR, dmso-d₆, δ (ppm): 2.95 (s, 3H); 3.40 (s, 3H); 4.45 (s, 2H); 7.64(t, 1H); 7.70 (t, 1H); 7.80 (dt, 1H); 7.91 (dd, 1H); 7.99-8.10 (m, 5H);8.65 (s, 1H).

Mass spectrum (ESI+): m/z 456 (MH⁺, 100%).

EXAMPLE 106[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-aceticacid methyl ester

The compound 106 was synthesized according to the procedure used forpreparing example 68 from the compound 105 (598 mg, 1.31 mmol). Theproduct is obtained as a beige powder (262 mg; 45%).

HPLC: RT=4.92 min, 97%

Mass spectrum (ESI+): m/z 442 (MH⁺, 100%).

EXAMPLES 107 TO 109

The compounds 107 to 109 were synthesized according to the procedureused for preparing examples 69 to 71 from the compound 106 and thecorresponding amines.

Mass Ex. NR₁R₂ Name of the compounds HPLC Yld. MH⁺ 107

2-[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yloxy]-1-piperidin-1-yl-ethanone 5.40′ 91% 64% 509 108

2-[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazin- 1-yl)-ethanone 3.99′ 99% 67% 524109

1-(4-Benzyl-piperazin-1-yl)-2-[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4- yloxy]-ethanone 4.35′ 98% 69% 600*¹H NMR, dmso-d₆, Ex. 107: 1.09-1.14 (m, 4 H); 1.31 (m, 2 H); 2.87 (t, 2H); 2.95 (s, 3 H); 3.05 (t, 2 H); 4.41 (s, 2 H); 7.64 (t, 1 H); 7.72 (t,1 H); 7.79 (dt, 1 H); 7.89 (dd, 1 H); 7.99-8.10 (m, 5 H); 8.64 (s, 1 H).Ex. 108: 1.86 (t, 2 H); 1.92 (t, 2 H); 1.96 (s, 3 H); 2.92-2.95 (m, 5H); 3.05 (t, 2 H); 4.44 (s, 2 H); 7.64 (t, 1 H); 7.72 (t, 1 H); 7.79(dt, 1 H); 7.90 (dd, 1 H); 7.98-8.10 (m, 5 H); 8.64 (s, 1 H). Ex. 109:1.90 (broad s, 2 H); 1.97 (broad s, 2 H); 2.92 (broad s, 2 H); 2.95 (s,3 H); 3.09 (broad s, 2 H); 3.22 (s, 2 H); 4.43 (s, 2 H); 7.16 (d, 2 H);7.21-7.31 (m, 3 H); 7.64 (t, 1 H); 7.72 (t, 1 H); 7.80 (dt, 1 H); 7.90(dd, 1 H); 7.98-8.09 (m, 5 H); 8.64 (s, 1 H).

EXAMPLE 110 Benzenesulfonic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester

The compound 17 (200 mg, 0.52 mmol) is dissolved in dichloromethane (2mL) and then treated at 0° C. with benzene sulfonyl chloride (67 μl,0.52 mmol) in the presence of Et₃N (145 μl, 1.04 mmol). The reaction isstirred from 0° C. to room temperature for 4 hours and then the mediumis taken up in dichloromethane and washed with water and with asaturated NaCl solution. The organic phases are combined, dried onmagnesium sulfate, filtered and concentrated. The thereby obtainedresidue is purified on a column of 12 g of silica (flow rate 12 mL/min,gradient of 20 to 50% dichloromethane in heptane), in order to obtainthe compound 110 as a cream-colored powder (177 mg; 65%).

HPLC: RT=5.72 min, 94%

¹H NMR, dmso-d₆, δ (ppm): 2.98 (s, 3H); 7.40 (t, 2H); 7.54-7.61 (m, 4H);7.66 (t, 1H); 7.75 (m, 2H); 7.84-7.90 (m, 2H); 8.04-8.09 (m, 3H); 8.57(s, 1H).

Mass spectrum (ESI+): m/z 541 (MNH₄ ⁺, 100%).

EXAMPLES 111 TO 117

The compounds 111 to 117 were synthesized according to the procedureused for preparing example 110 from the compound 1 or 17 and thecorresponding sulfonyl chlorides.

Mass MH⁺/ Ex. R1 R2 Name of the compounds HPLC Yld. MNa⁺ 111 H HBenzenesulfonic acid 2- 5.59′ 71% 506 methyl-3-(naphthalene-2- 99%carbonyl)-1,1-dioxo-2H- benzo[e][1,2]thiazin-4-yl ester 112 H Cl4-Chloro-benzenesulfonic 5.84′ 94% 540 acid 2-methyl-3- 99%(naphthalene-2-carbonyl)- 1,1-dioxo-2H- benzo[e][1,2]thiazin- 4-yl ester113 H Me 4-Methyl-benzenesulfonic 5.74′ 93% 520 acid 2-methyl-3- 99%(naphthalene-2-carbonyl)- 1,1-dioxo-2H- benzo[e][1,2]thiazin- 4-yl ester114 H CN 4-Cyano-benzenesulfonic acid 5.50′ 89% 5312-methyl-3-(naphthalene-2- 99% carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin- 4-yl ester 115 F Cl 4-Chloro-benzenesulfonic 5.96′55% 558 acid 7-fluoro-2-methyl-3- 96% 580 (naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yl ester 116 F Me4-Methyl-benzenesulfonic 5.88′ 59% 538 acid 7-fluoro-2-methyl-3- 97% 560(naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2] thiazin-4-yl ester117 F CN 4-Cyano-benzenesulfonic acid 5.59′ 56% 549 7-fluoro-2-methyl-3-97% 571 (naphthalene-2-carbonyl)- 1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester

EXAMPLE 118(4-Hydroxy-2-methyl-7-piperidin-1-yl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

The compound 17 (200 mg, 0.52 mmol) is dissolved in DMSO (2 mL) in thepresence of K₂CO₃ (144 mg, 1.04 mmol) and then treated at roomtemperature with piperidine (154 μl, 1.56 mmol). The reaction is stirredat 100° C. for 20 hours and then the medium is taken up in ethyl acetateand washed with water and with a saturated NaCl solution. The organicphases are combined, dried on magnesium sulfate, filtered andconcentrated. The thereby obtained residue is purified on a column of 12g of silica (flow rate 12 mL/min, gradient of 0 to 50% ethyl acetate inheptane) in order to obtain the compound 118 as a yellow powder (22 mg;9.5%).

HPLC: RT=6.39 min, 96%

¹H NMR, dmso-d₆, δ (ppm): 1.64 (broad s, 6H); 2.63 (s, 3H); 3.57 (broads, 4H); 7.22 (d, 1H); 7.34 (dd, 1H); 7.65-7.70 (m, 2H); 7.96 (d, 1H);8.03 (d, 1H); 8.09-8.11 (m, 3H); 8.62 (s, 1H).

Mass spectrum (ESI+): m/z 449 (MH⁺, 100%).

EXAMPLES 119 TO 121

The compounds 119 to 121 were synthesized according to the procedureused for preparing example 118 from the compound 17 and thecorresponding amines.

Mass MH⁺/ Ex. NR₁R₂ Name of the compounds HPLC Yld. M − H⁻ 119 NMe₂(7-Dimethylamino-4-hydroxy-2-methyl-1,1- 5.86′ 35% 409dioxo-2H-benzo[e][1,2]thiazin-3-yl)- 100% naphthalen-2-yl-methanone 120

(4-Hydroxy-2-methyl-7-pyrrolidin-1-yl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)- naphthalen-2-yl-methanone 6.18′100% 13% 435 121

[4-Hydroxy-2-methyl-7-(4-phenyl-piperazin-1-yl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]- naphthalen-2-yl-methanone6.18′ 94% 93% 524

EXAMPLE 122(7-tertButyl-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone

The compound 122 was synthesized from2-methyl-5-tertbutylbenzenesulfonyl chloride according to the samesequence of steps involved in preparing the compound 17. The compound isobtained as a yellow solid with an overall yield of 10%.

HPLC: RT=6.33 min, 95%

¹H NMR, dmso-d₆, δ (ppm): 1.38 (s, 9H); 2.65 (s, 3H); 7.66 (t, 1H); 7.72(t, 1H); 7.88 (s, 1H); 8.05 (d, 2H); 8.12-8.17 (m, 4H); 8.65 (s, 1H);15.69 (s, 1H, exch).

Mass spectrum (ESI+): m/z 422 (MH⁺, 100%).

EXAMPLES 123 TO 130

The compounds 123 to 130 were synthesized from saccharine and fromcorresponding 2-bromo-1-arylethanones according to the same sequence ofsteps described for preparing the compound 1 (for 123, 125, 127 and 128)from the compound 8 (for 124 and 126) and from the compound 17 (for 129and 130)

Mass Ex. R1 R2 Ar Name of the compounds HPLC Yld. ¹ MH⁺/M-H⁻ 123 Me H3,4-dichlorophenyl (4-hydroxy-2-methyl-1,1- 5.88′ 60% 382 & 384dioxo-2H- 99% benzo[e][1,2]thiazin-3- yl) (3,4- dichlorophenyl)methanone124 Et H 3,4-dichlorophenyl (4-hydroxy-2-ethyl-1,1- 6.07′ 64% 396 & 398dioxo-2H- 99% benzo[e][1,2]thiazin-3- yl) (3,4- dichlorophenyl)methanone125 Me H benzofuran-2-yl (4-hydroxy-2-methyl-1,1- 5.31′ 68% 356dioxo-2H- 99% benzo[e][1,2]thiazin-3- yl) (benzofuran-2- yl)methanone126 Et H benzofuran-2-yl (4-hydroxy-2-ethyl-1,1- 5.54′ 63% 370 dioxo-2H-99% benzo[e][1,2]thiazin-3- yl) (benzofuran-2- yl)methanone 127 Me H5,6,7,8-tetrahydro-naphthalen-2-yl (4-Hydroxy-2-methyl-1,1- 6.04′ 60%370 dioxo-2H- 100% benzo[e][1,2]thiazin-3- yl)-(5,6,7,8-tetrahydro-naphthalen-2-yl)- methanone 128 Me H 5,5,8,8-tetramethyl-5,6,7,(4-Hydroxy-2-methyl-1,1- 6.66′ 70% 426 8-tetrahydro-naphthalen-2-yldioxo-2H- 100% benzo[e][1,2]thiazin-3- yl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- naphthalen-2-yl)- methanone 129 Me F5,6,7,8-tetrahydro-naphthalen-2-yl (7-Fluoro-4-hydroxy-2- 6.14′ 68% 386methyl-1,1-dioxo-2H- 95% benzo[e][1,2]thiazin-3-yl)-(5,6,7,8-tetrahydro- naphthalen-2-yl)- methanone 130 Me F5,5,8,8-tetramethyl-5,6,7,8- (7-Fluoro-4-hydroxy-2- 6.75′ 80% 442tetrahydro-naphthalen-2-yl methyl-1,1-dioxo-2H- 93%benzo[e][1,2]thiazin-3- yl)-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydro-naphthalen-2-yl)- methanone ¹ Overall yield for the 3 steps. * ¹H NMR,dmso-d₆, Ex. 123: 2.68 (s, 3H); 7.95 (d, 1H); 7.98-8.00 (m, 4H); 8.16(d, 1H); 8.19-8.21 (m, 1H); 14.93 (s, 1H, exch). Ex. 124: 0.55 (t, 3H);3.16 (q, 2H); 7.92 (d, 1H); 7.97-7.98 (m, 4H); 8.16 (d, 1H); 8.19-8.20(m, 1H); 14.77 (s, 1H, exch). Ex. 125: 2.98 (s, 3H); 7.43 (t, 1H); 7.62(dt, 1H); 7.80 (d, 1H); 7.99-8.04 (m, 4H); 8.20 (se, 1H); 8.34 (s, 1H);15.56 (se, exch., 1H). Ex. 126: 0.67 (t, 3H); 3.57 (q, 2H); 7.43 (t,1H); 7.63 (dt, 1H); 7.80 (d, 1H); 7.96-8.18 (m, 4H); 8.20 (se, 1H); 8.31(s, 1H); 15.33 (se, exch., 1H). Ex. 127: 1.78 (s, 4H); 2.64 (s, 3H);2.81 (s, 4H); 7.30 (d, 1H); 7.45 (s, 1H); 7.86 (d, 1H); 7.98 (m, 3H);8.18-8.21 (m, 1H); 15.75 (s, 1H). Ex. 128: 1.30 (d, 12H); 1.70 (s, 4H);2.64 (s, 3H); 7.58 (d, 1H); 7.78 (d, 1H); 7.98 (m, 3H); 8.18-8.21 (m,1H); 8.25 (d, 1H); 15.62 (s, 1H). Ex. 129: 1.77 (broad s, 4H) ; 2.67 (s,3H) ; 2.80 (broad s, 4H); 7.23 (broad s, 1H); 7.60-7.85 (m, 4H); 8.21(m, 1H); 15.85 (s, 1H). Ex. 130: 1.28 (d, 12H); 1.69 (s, 4H); 2.65 (s,3H); 7.51 (d, 1H); 7.66 (d, 1H); 7.88 (m, 2H); 8.08 (broad s, 1H) ; 8.21(q, 1H) ; 15.65 (s, 1H).

EXAMPLES 131 TO 143

The compounds 131 to 143 were synthesized from saccharine and from thecorresponding 2-bromo-1-arylethanones according to the same sequence ofsteps described for preparing the compound 1 (R2=Me) or the compound 8(R2=Et).

Ex.* R1 R2 Name of the compounds HPLC Yld.¹ MH⁺ 131

Me (2,3-Dihydro-benzofuran-5-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3- yl)-methanone 5.59′ 98% 24% 358 132

Et (2,3-Dihydro-benzofuran-5-yl)-(4- hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3- yl)-methanone 5.75′ 98% 23% 372 133

Me Benzo[1,3]dioxol-5-yl-(4-hydroxy-2- methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone 5.50′ 99% 34% 360 134

Et Benzo[1,3]dioxol-5-yl-(4-hydroxy-2- ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone 5.66′ 97% 34% 374 135

Me (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)- methanone 5.53′ 96% 45% 374 136

Et (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone 5.68′ 99% 42% 388 137

Me Benzo[b]thiophen-5-yl-(4-hydroxy-2- methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone 5.56′ 99% 31% 372 138

Me Benzofuran-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e] [1,2]thiazin-3-yl)-methanone 5.34′ 99%36% 356 139

Me (4-Hydroxy-2-methyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-methyl-1H-benzoimidazol-5- yl)-methanone 3.72′ 99% 5% 370 140

Me Benzo[b]thiophen-2-yl-(4-hydroxy-2- methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone 5.89′ 99% 48% 372 141

Me (4-tert-Butyl-phenyl)-(4-hydroxy-2- methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone 6.97′ 99%** 32% 372 142

Me (3-Bromo-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e] [1,2]thiazin-3-yl)-methanone 6.47′99%** 57% 394/ 396 143

Me 3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3- carbonyl)-benzonitrile 5.84′ 93%**37% 358 ¹Overall yield for the 3 steps. *¹H NMR, dmso-d₆, Ex. 131: 2.68(s, 3 H); 3.33 (m, 2 H); 4.69 (t, 2 H); 7.02 (d, 1 H); 7.97-7.98 (m, 3H); 8.03 (s, 1 H); 8.08 (dd, 1 H), 8.18-8.20 (m, 1 H); 16.03 (s, 1 H,exch). Ex. 132: 0.55 (t, 3 H); 3.18 (q, 2 H); 3.28-3.34 (m, 2 H); 4.69(t, 2 H); 7.00 (d, 1 H); 7.94-7.98 (m, 4 H); 8.03 (d, 1 H); 8.17-8.19(m, 1 H); 15.77 (s, 1 H, exch). Ex. 133: 2.69 (s, 3 H); 6.21 (s, 2 H);7.19 (d, 1 H); 7.56 (d, 1 H); 7.82 (dd, 1 H); 7.96-7.99 (m, 3 H);8.18-8.20 (m, 1 H); 15.66 (s, 1 H, exch). Ex. 134: 0.56 (t, 3 H); 3.18(q, 2 H); 6.20 (s, 2 H); 7.18 (d, 1 H); 7.53 (d, 1 H); 7.77 (dd, 1 H);7.94-7.96 (m, 3 H); 8.17-8.19 (m, 1 H); 15.39 (s, 1 H, exch). Ex. 135:0.55 (t, 3 H); 3.18 (q, 2 H); 4.33 (t, 2 H); 4.37 (t, 2 H); 7.09 (d, 1H); 7.64 (d, 1 H); 7.67 (dd, 1 H); 7.94-7.96 (m, 3 H); 8.17-8.19 (m, 1H); 15.55 (s, 1 H, exch). Ex. 136: 0.55 (t, 3 H); 3.18 (q, 2 H); 4.33(t, 2 H); 4.37 (t, 2 H); 7.09 (d, 1 H); 7.64 (d, 1 H); 7.67 (dd, 1 H);7.94-7.96 (m, 3 H); 8.17-8.19 (m, 1 H); 15.55 (s, 1 H, exch). Ex. 137:2.65 (s, 3 H); 7.69 (d, 1 H); 7.96 (d, 1 H); 7.98-8.00 (m, 3 H); 8.07(d, 1 H); 8.21-8.23 (m, 1 H); 8.28 (d, 1 H); 8.60 (s, 1 H); 15.69 (s, 1H, exch). Ex. 138: 2.64 (s, 3 H); 7.22 (d, 1 H); 7.86 (d, 1 H);7.98-8.00 (m, 3 H); 8.09 (dd, 1 H); 8.19 (d, 1 H); 8.21-8.45 (m, 1 H);8.45 (s, 1 H); 15.71 (s, 1 H, exch). Ex. 139: 2.63 (s, 3 H); 3.92 (s, 3H); 7.81 (d, 1 H); 7.98-8.05 (m, 4 H); 8.20-8.23 (m, 1 H); 8.52 (s, 1H); 8.52 (s, 1 H); 15.87 (s, 1 H, exch). Ex. 140: 2.97 (s, 3 H); 7.53(t, 1 H); 7.61 (t, 1 H); 8.00-8.02 (m, 3 H); 8.17-8.22 (m, 3 H); 8.67(s, 1 H); 15.70 (s, 1 H, exch). Ex. 141: 1.34 (s, 9 H), 2.66 (s, 3 H);7.66 (d, 2 H); 7.98-8.00 (m, 3 H); 8.06 (d, 2 H); 8.18-8.21 (m, 1 H);15.71 (s, 1 H, exch). Ex. 142: 2.65 (s, 3 H); 7.60 (t, 1 H); 7.90 (d, 1H); 7.95-8.05 (m, 4 H); 8.11 (s, 1 H); 8.19 (broad s, 1 H); 15.06 (s, 1H, exch). Ex. 143: 2.65 (s, 3 H); 7.84 (t, 1 H); 7.95-8.00 (m, 3 H);8.15-8.21(m, 2 H); 8.28-8.31 (m , 2 H); 14.86 (broad s, 1 H, exch).**XBridge column

EXAMPLES 144 TO 146

The compounds 144 to 146 were synthesized from saccharine and from thecorresponding 2-bromo-1-arylethanones according to the same sequence ofsteps described for the preparation of the compound 1.

The 2-bromo-1-arylethanones were prepared by bromination of thecorresponding arhylethanones, according to the procedure described forpreparing the compound 144A: 1-(3,4-dimethylphenyl)ethanone (2.5 g, 16.9mmol) is dissolved under a nitrogen atmosphere in 42 mL of THF at roomtemperature. Trifluoroacetic acid (1.5 mL, 16.9 mmol) is added followedby pyridinium tribromide (6.5 g, 20.2 mmol). The solution turnsvermilion red and a white precipitate gradually appears. After threehours of stirring at room temperature, the reaction is neutralized byadding 50 mL of water, and then extracted with 100 mL of ethyl acetate.The organic phase is washed with 40 mL of a saturated CuSO₄ solution, 40mL of a saturated NaCl solution, and then dried on magnesium sulfate,filtered and concentrated under reduced pressure. The residue ispurified on a column of 130 of silica with a gradient of 0% to 5% ethylacetate in heptane in order to obtain two batches of2-bromo-1-(3,4-dimethyl-phenyl)-ethanone (144A, 57%).

Batch 1: 1.25 g; HPLC: RT=4.90 min, 90%.

Batch 2: 1.90 g; HPLC: RT=4.90 min, 70%.

Ex.* R1 Name of the compounds HPLC Yld.¹ MH+ 144

(3,4-Dimethyl-phenyl)-(4-hydroxy- 2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)- methanone  5.62′ 99% 27% 344 145

(4-Hydroxy-2-methyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-trifluoromethyl-phenyl)- methanone  6.56′ 99%** 23% 384 146

(4-Hydroxy-2-methyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4-trifluoromethyl-phenyl)- methanone  6.64′ 99%** 17% 384 ¹Overallyield for the 4 steps. *¹H NMR, dmso-d₆, Ex. 144: 2.33 (s, 3H); 2.34 (s,3H); 2.63 (s, 3H); 7.40 (d, 1H); 7.82 (s, 1H); 7.90 (d, 1H); 7.98-8.00(m, 3H); 8.18-8.21 (m, 1H); 15.73 (s, 1H, exch). Ex. 145: 2.65 (s, 3H);7.89 (t, 1H); 8.00-8.01 (m, 3H); 8.08 (d, 1H); 8.20-8.22 (m, 1H); 8.30(broad s, 2H) , 15.00 (broad s, 1H, exch). Ex. 146: 2.64 (s, 3H);8.00-8.03 (m, 5H); 8.17-8.21 (m, 3H); 15.06 (broad s, 1H, exch).**XBridge column.

EXAMPLE 147

Adamantan-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

EXAMPLE 147A Adamantane-2-carbonitrile

Adamantanone (2.5 g, 16.6 mmol) is dissolved under an nitrogenatmosphere under 58 mL of 1,2-dimethoxyethane (DME) in the presence ofethanol (1.7 mL) and of TosMIC (4.22 g, 21.6 mmol). The reaction mediumis cooled with an ice bath. Potassium tert-butylate (5.72 g, 51 mmol) isslowly added, while maintaining the temperature of the reaction mediumbetween 2° C. and 11° C. The reaction is stirred for 30 minutes between5° C. and 12° C. before being brought back to room temperature andstirring is continued for 2 hours. The reaction medium is filtered andthe white precipitate is rinsed with DME. The filtrate is concentrated.The thereby obtained residue is purified on silica (5% ethyl acetate inheptane), in order to obtain the compound 147A as a white solid (2.38 g,88%).

¹H NMR, dmso-d₆, δ (ppm): 1.65-1.95 (m, 12H); 2.07 (broad s, 2H); 3.14(broad s, 1H).

Mass spectrum (ESI+): m/z 162 (MH⁺, 20%); 194 (MH⁺.MeOH, 100%).

EXAMPLE 147B 1-Adamantan-2-yl-ethanone

The compound 147A (4.63 g, 28.7 mmol) is dissolved under a nitrogenatmosphere in 61 mL of ether, and then cooled with an ice bath.Methyllithium (27 mL, 1.6 M/Et₂O, 43 mmol) is added dropwise whilemaintaining the reaction medium between 5° C. and 12° C. As soon as theaddition is finished, the cold bath is removed and stirring is continuesfor 30 minutes at room temperature. The reaction medium is thenneutralized with 46 ml of water. The organic phase is recovered, driedon magnesium sulfate, dried and concentrated under reduced pressure. Theresidue is taken up in 28 mL of acetone and 28 mL of 6N HCl, and thenrefluxed for heating for 80 minutes. The acetone is then evaporated andthe residual aqueous phase is extracted twice with ethyl acetate. Theorganic phases are combined, dried on magnesium sulfate, filtered andconcentrated. The thereby obtained residue is purified on a column of 90g of silica (32 mL/min, 6% ethyl acetate in heptane), in order to obtainthe compound 147B as a yellow solid (3.66 g, 71%).

¹H NMR, dmso-d₆, δ (ppm): 1.45-1.55 (m, 2H); 1.65-1.90 (m, 10H); 2.09(s, 3H); 2.29 (broad s, 2H); 2.54 (broad s, 1H).

Mass spectrum (ESI+): m/z 179 (MH⁺, 100%).

EXAMPLE 147C 1-Adamantan-2-yl-2-bromo-ethanone

The compound 147B (500 mg, 2.8 mmol) is dissolved in 8.6 mL of methanolunder a nitrogen atmosphere, and then cooled to 0° C. Bromine (151 μl,2.94 mmol) is slowly added. The reaction medium is stirred for 1 h 40min at 0° C. and then neutralized with water and extracted twice withethyl acetate. The organic phases are combined, dried on magnesiumsulfate, filtered and concentrated. The thereby obtained residue ispurified on a column of 35 g of silica (20 mL/min, gradient of 0% to 15%ethyl acetate in heptane in 25 minutes), in order to obtain the compound147C (1.37 g, 85%).

¹H NMR, dmso-d₆, (ppm): 1.5-1.6 (m, 2H); 1.65-1.90 (m, 10H); 2.38 (broads, 2H); 2.86 (broad s, 1H); 4.45 (s, 2H).

EXAMPLE 147Adamantan-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

The compound 147 was synthesized from saccharin and from the compound147C according to the same sequence of steps described for preparing thecompound 1 with a yield of 11% for the three steps.

White solid

HPLC: RT=6.28 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 1.54-1.61 (m, 2H); 1.68-1.93 (m, 8H);2.05-2.25 (m, 2H); 2.36 (broad s, 2H); 2.89 (s, 3H); 3.27 (s, 1H);7.93-7.96 (m, 3H); 8.08-8.11 (m, 1H); 15.22 (s, 1H, exch).

Mass spectrum (ESI−): m/z 372 (M-H⁻, 100%).

EXAMPLE 148Chroman-6-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

EXAMPLE 148A Chromane

4-chromanone (5.0 g, 33.7 mmol) is dissolved in 102 mL of THF under anitrogen atmosphere. BF₃.OEt₂ (12.8 mL, 101 mmol) is added at roomtemperature and sodium cyanoborohydride (4.33 g, 67.4 mmol) is addedslowly (violent reaction). The thereby obtained white suspension isheated to 65° C. of 18 hours, and then neutralized with water. Thereaction mixture is extracted twice with ethyl acetate. The organicphases are combined, successively washed with a saturated NaHCO₃solution and a saturated NaCl solution, and then dried on magnesiumsulfate, filtered and concentrated under reduced pressure. The therebyobtained residue is purified on silica (gradient of 0% to 50%dichloromethane in heptane, and then 10% ethyl acetate in heptane), inorder to obtain the partly purified compound 148A (3.34 g, 61%).

HPLC: RT=4.56 min, 83%

¹H NMR, dmso-d₆, δ (ppm): 1.91 (q, 2H); 2.72 (t, 2H); 4.11 (t, 2H); 6.70(d, 1H); 6.80 (t, 1H); 7.0-7.05 (m, 2H).

EXAMPLE 148B 1-Chroman-6-yl-ethanone

Chromane (4.64 g, 29.4 mmol) is dissolved in 30 mL of anhydrousdichloromethane (DCM) under a nitrogen atmosphere. The reaction mediumis cooled to −30° C., and then a cold solution (−10° C.) of ethanoylchloride (4.75 mL, 67 mmol) in 20 mL of anhydrous DCM is added within 5minutes. The mixture is stirred for 45 min at −15° C., and then pouredover a mixture of 100 g of ice and 50 mL of concentrated HCl andextracted three times with DCM. The organic phases are combined, driedon magnesium sulfate, filtered and concentrated under reduced pressure.The thereby obtained residue is purified on a column of 120 g of silica(gradient of 0% to 20% EtOAc in heptane in 60 minutes), in order toobtain two batches of compound 148B (70%).

Batch 1: 2.25 g; HPLC: RT=4.09 min, 96.6%.

¹H NMR, dmso-d₆, δ (ppm): 1.93 (q, 2H); 2.49 (s, 3H); 2.79 (t, 2H); 4.21(t, 2H); 6.81 (d, 1H); 7.65-7.75 (m, 2H).

Mass spectrum (ESI+): m/z 177 (MH⁺, 100%).

Batch 2: 1.79 g; HPLC: RT=4.09 min, 81%.

EXAMPLE 148C 2-Bromo-1-chroman-6-yl-ethanone

The compound 148C was synthesized from the compound 148B according tothe procedure for preparing the compound 144A, with a yield of 65%.

HPLC: RT=4.59 min, 74%.

¹H NMR, dmso-d₆, (ppm): 1.95 (q, 2H); 2.80 (t, 2H); 4.20 (t, 2H); 4.80(s, 2H); 6.85 (d, 1H); 7.70-7.85 (m, 2H).

EXAMPLE 148Chroman-6-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

The compound 148 was synthesized from saccharin and from the compound148C according to the same sequence of steps described for preparing thecompound 1, with an overall yield of 36%.

HPLC: RT=5.45 min, 98%

¹H NMR, dmso-d₆, δ (ppm): 1.98 (t, 2H); 2.69 (s, 3H); 2.84 (t, 2H); 4.27(t, 2H); 6.96 (d, 1H); 7.89 (s, 1H); 7.97-8.02 (m, 4H); 8.17-8.18 (m,1H); 16.02 (s, 1H, exch).

Mass spectrum (ESI+): m/z 372 (MH⁺, 100%).

EXAMPLE 149(4-Chloro-3-trifluoromethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

EXAMPLE 149A 1-(4-Chloro-3-trifluoromethyl-phenyl)-ethanol

4-chloro-3-trifluoromethyl-benzaldehyde (6.19 g, 29.7 mmol) is dissolvedin 124 mL of THF under a nitrogen atmosphere. The reaction medium iscooled to −78° C. before adding dropwise MeMgBr (13 mL, 3M/Et₂O, 38.6mmol), and then stirred for a further 2 hours at this low temperature,and finally neutralized by adding 60 mL of a saturated NH₄Cl solution.The reaction medium is extracted twice with ethyl acetate. The organicphases are combined, washed with a saturated NaCl solution, and thendried on magnesium sulfate, filtered and concentrated under reducedpressure. The thereby obtained residue is purified on a column of 120 gof silica (92 mL/min; gradient of 0% to 35% ethyl acetate in heptane in40 min), in order to obtain the compound 149A (5.71 g, 62%).

HPLC: RT=5.71 min, 98% (colonne XBridge)

¹H NMR, dmso-d₆, δ (ppm): 1.33 (d, 3H); 4.81 (quintet, 1H); 5.46 (d, 1H,exch); 7.60-7.69 (m, 2H); 7.81 (s, 1H).

EXAMPLE 149B 1-(4-Chloro-3-trifluoromethyl-phenyl)-ethanone

The compound 149A (2.62 g, 11.7 mmol) is dissolved in 53 mL of DCM inthe presence of 3.8 g of celite. PCC (3.77 g, 17.5 mmol) is added atroom temperature and the reaction medium is stirred overnight beforebeing filtered. The filtrate is concentrated under reduced pressure. Thethereby obtained residue is purified on a column of 80 g of silica (32mL/min, gradient of 0% to 30% EtOAc in heptane in 26 minutes), in orderto obtain the compound 149B (2.27 g, 87%).

HPLC: RT=5.84 min, 97% (colonne XBridge)

¹H NMR, dmso-d₆, δ (ppm): 2.65 (s, 3H); 7.92 (d, 1H); 8.22-8.27 (m, 2H).

EXAMPLE 149C 2-Bromo-1-(4-chloro-3-trifluoromethyl-phenyl)-ethanone

The compound 149C was synthesized from the compound 149B according tothe procedure for preparing the compound 144A, with a yield of 66%.

HPLC: RT=6.18 min, 89% (colonne XBridge)

¹H NMR, dmso-d₆, δ (ppm): 5.05 (s, 2H); 7.96 (d, 1H); 8.28 (d, 1H); 8.34(s, 1H).

EXAMPLE 149(4-Chloro-3-trifluoromethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

The compound 149 was synthesized from saccharin and from the compound149C according to the same sequence of steps described for preparing thecompound 1, with an overall yield of 20%.

HPLC: RT=6.71 min, 99% (XBridge column)

¹H NMR, dmso-d₆, (ppm): 2.68 (s, 3H); 7.98-8.04 (m, 4H); 8.18-8.21 (m,1H); 8.29 (d, 1H); 8.40 (s, 1H); 14.82 (s, 1H, exch).

Mass spectrum (ESI−): m/z 416 (M-H⁻, 100%); 418 (M-H⁻, 25%).

EXAMPLE 150(7-Bromo-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

EXAMPLE 150A 4-Bromo-2-sulfamoyl-benzoic acid

5-bromo-2-methyl-benzenesulfonamide (2.5 g, 9.99 mmol) is dissolved in62 mL of soda (5% in water). The reaction is heated to 100° C. and KMnO₄(6.43 g, 25 mmol) is gradually added within 15 minutes. Heating iscontinued for 140 minutes. The reaction medium is cooled to roomtemperature and then filtered. The pH of the filtrate is brought back to1.2 with a concentrated HCl solution, and then filtered. The precipitateis rinsed with ethyl acetate. The two phases of the filtrate areseparated and the aqueous phase is extracted once with ethyl acetate.The organic phases are collected, dried on magnesium sulfate, filteredand concentrated under reduced pressure, in order to obtain the compound150A (1.64 g, 58%).

HPLC: RT=0.29 min, 99.5%

¹H NMR, dmso-d₆, δ (ppm): 7.35 (s, 2H, exch); 7.67 (d, 1H); 7.91 (d,1H); 8.08 (s, 1H); 13.83 (broad s, 1H, exch).

Mass spectrum (ESI−): m/z 278 (M-H⁻, 100%); 280 (M-H⁻, 87%).

EXAMPLE 150B 6-BROMO-1,1-DIOXO-1,2-DIHYDRO-2H-BENZO[d]isothiazol-3-one

The compound 150A (1.59 g, 5.56 mmol) is dissolved in 6 mL ofconcentrated sulfuric acid at room temperature and the reaction mediumis stirred for 3 hours before being poured over ice. The suspension isfiltered. The precipitate is rinsed three times with water, and thendried for 24 hours at 50° C. and in vacuo. The compound 150B (1.33 g,89%) is obtained as a white solid.

HPLC: RT=3.16 min, 96%

¹H NMR, dmso-d₆, δ (ppm): 7.85 (d, 1H); 8.08 (d, 1H); 8.48 (s, 1H).

Mass spectrum (ESI−): m/z 260 (M-H⁻, 100%); 262 (M-H⁻, 94%).

EXAMPLE 150(7-Bromo-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

The compound 150 was synthesized from the compound 150B and from2-bromo-1-(naphthalen-2-yl)ethanone according to the same sequence ofsteps described for preparing the compound 1, with an overall yield of55%.

HPLC: RT=6.14 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 2.68 (s, 3H); 7.66 (t, 1H); 7.73 (t, 1H);8.04-8.15 (m, 5H); 8.19-8.22 (m, 2H); 8.65 (s, 1H); 15.38 (s, 1H, exch).

Mass spectrum (ESI+): m/z 444 (MH⁺, 100%); 446 (MH⁺, 99%).

EXAMPLE 151(7-Chloro-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

EXAMPLE 151A 6-Chloro-1,1-dioxo-1,2-dihydro-2H-benzo[d]isothiazol-3-one

Methyl 2-amino-4-chlorobenzoate (5 g, 26.9 mmol) is heated in 18 mL ofHCl (20% in water) until complete dissolution, and then cooled to 0° C.A solution of NaNO₂ (1.85 g, 26.9 mmol) in 4.5 mL of water is addeddropwise while maintaining the temperature between 2° C. and 6° C. Thereaction medium is then stirred for 1 hour at room temperature. In asecond flask, about 15 g of SO₂ gas is bubbled in 22 mL of acetic acidand 2.3 mL of water at 0° C. CuCl (666 mg, 6.7 mmol) is then added. Thefirst reaction medium is then added to this blue-green solution between1° C. and 3° C. Gas evolvement is observed; Stirring at low temperatureis continued for 45 minutes before removing the cold bath, and then thereaction medium is poured over 100 g of ice and extracted three timeswith ethyl acetate. The organic phases are collected, washed with asaturated NaHCO₃ solution, dried on magnesium sulfate, filtered andconcentrated under reduced pressure. The residue is taken up into 5 mLof THF at 0° C. and 2.8 mL of a concentrated ammonia solution are addedslowly. The cold bath is removed and stirring is continued for 1 hour.The reaction medium is concentrated, taken up with a saturated NaHCO₃,solution, washed once with ether, and then brought back to pH=1 with aconcentrated HCl solution. The formed precipitate is filtered, rinsedwith water and dried under reduced pressure at 50° C. in order to obtainthe compound 151A (896 mg, 15%).

HPLC: RT=3.07 min, 99%

¹H NMR, dmso-d₆, δ (ppm): 7.94 (broad d, 2H); 8.38 (s, 1H).

Mass spectrum (ESI−): m/z 216 (M-H⁻, 100%); 218 (M-H⁻, 32%).

EXAMPLE 151(7-Chloro-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

The compound 151 was synthesized from the compound 151A and from2-bromo-1-(naphthalen-2-yl)ethanone according to the same sequence ofsteps described for preparing the compound 1, with an overall yield of39%.

HPLC: RT=6.13 min, 95%

¹H NMR, dmso-d₆, δ (ppm): 2.68 (s, 3H); 7.66 (t, 1H); 7.74 (t, 1H);8.03-8.16 (m, 6H); 8.21 (d, 1H); 8.65 (s, 1H); 15.41 (se, 1H, exch).

Mass spectrum (ESI−): m/z 398 (M-H⁻, 100%); 400 (M-H⁻, 32%).

EXAMPLE 152(4-Hydroxy-2,7-dimethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

EXAMPLE 152A 2-Cyano-5-methyl-benzenesulfonamide

2-amino-4-methyl-benzonitrile (2.5 g, 18.9 mmol) is heated in 12 mL ofHCl (20% in water) until complete dissolution), and then cooled to 0° C.A solution of NaNO₂ (1.3 g, 18.9 mmol) in 3.2 mL of water is addeddropwise while maintaining the temperature between 2° C. and 6° C. Thereaction medium is then stirred for 1 hour at room temperature. In asecond flask, about 15.7 g of SO₂ gas is bubbled in 15 mL of acetic acidand 1.6 mL of water at 0° C. CuCl (468 mg, 4.7 mmol) is then added. Thefirst reaction medium is then added to this blue-green solution between1° C. and 3° C. Gas evolvement is observed. Stirring at low temperatureis continued for 45 minutes before removing the cold bath, and then thereaction mixture is poured over 70 g of ice and extracted three timeswith a mixture of 20% methanol in DCM. The organic phases are collected,washed with a saturated NaHCO₃ solution, dried on magnesium sulfate,filtered and concentrated under reduced pressure. The residue is takenup into 5 mL of THF at 0° C. and 2.8 mL of a concentrated ammoniasolution are added slowly. The cold bath is removed and stirring iscontinued for 1 hour. The reaction medium is concentrated, taken up witha saturated NaHCO₃ solution, washed once with ether, and then broughtback to pH=1 with a concentrated HCl solution. The formed precipitate isfiltered, rinsed with water and dried under reduced pressure at 50° C.in order to obtain the compound 152A (800 mg, 21%).

HPLC: RT=3.67 min, 99% (colonne XBridge)

¹H NMR, dmso-d₆, δ (ppm): 7.61 (d, 1H); 7.77 (s, 1H); 7.99 (d, 1H); 8.77(broad s, 2H).

Mass spectrum (ESI+): m/z 197 (MH⁺, 100%).

EXAMPLE 152B 4-Methyl-2-sulfamoyl-benzoic acid

The compound 152A (620 mg, 3.15 mmol) is dissolved in 7.5 mL of KOH (30%in water) and 530 μl of hydrogen peroxide (30% in water). The reactionmedium is refluxed with heating for 4 hours, and then cooled to roomtemperature, brought back to pH=1 with a concentrated HCl solution andextracted three times with a mixture of 20% methanol in DCM. The organicphases are collected, dried on magnesium sulfate, filtered andconcentrated under reduced pressure, in order to obtain the compound152B (428 g, 60%).

HPLC: RT=4.11 min, 95% (colonne XBridge)

¹H NMR, dmso-d₆, δ (ppm): 2.41 (s, 3H); 7.19 (broad s, 2H, exch); 7.48(d, 1H); 7.65 (d, 1H); 7.77 (s, 1H); 12.5-14.5 (broad s, 1H, exch).

Mass spectrum (ESI−): m/z 214 (M-H⁻, 100%).

EXAMPLE 152C 6-Methyl-1,1-dioxo-1,2-dihydro-2H-benzo[d]isothiazol-3-one

The compound 152B (428 mg, 1.94 mmol) is dissolved in 3 mL ofconcentrated sulfuric acid at room temperature. The reaction mixture isstirred for 2 hours and then poured over ice and filtered. Theprecipitate is abundantly rinsed with water and then dried in order toobtain the compound 152C (359 mg, 93%) as a pink solid.

HPLC: RT=4.00 min, 96% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 7.74 (d, 1H); 7.89 (d, 1H); 8.00 (s, 1H).

Mass spectrum (ESI−): m/z 196 (M-H⁻, 100%).

EXAMPLE 152(4-Hydroxy-2,7-dimethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

The compound 152 was synthesized from the compound 152C and from2-bromo-1-(naphthalen-2-yl)ethanone according to the same sequence ofsteps described for preparing the compound 1, with an overall yield of21%.

HPLC: RT=6.87 min, 98% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 2.55 (s, 3H); 2.64 (s, 3H); 7.66 (t, 1H); 7.72(t, 1H); 7.80 (d, 1H); 7.84 (s, 1H); 8.05 (d, 1H); 8.11-8.11 (m, 4H);8.67 (s, 1H); 15.75 (s, 1H, exch).

Mass spectrum (APCI+): m/z 380 (MH⁺, 24%).

EXAMPLE 153Biphenyl-3-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

EXAMPLE 153Biphenyl-3-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone

The compound 142 (200 mg, 0.5 mmol) is dissolved under an inertatmosphere in 1.1 mL of acetone and 1.2 mL of water in the presence ofbenzene boronic acid (68 mg, 0.55 mmol), of potassium carbonate (175 mg,1.27 mmol) and palladium acetate (5 mg, 0.02 mmol). The reaction mixtureis heated to 85° C. for 1 hour and 30 minutes and then brought back toroom temperature, diluted with water and extracted three times with DCM.The organic phases are combined, dried on magnesium sulfate, filteredand concentrated under reduced pressure. The thereby obtained residue ispurified on a column of 12 g of silica with DCM, in order to obtain thecompound 153 (141 mg, 68%).

HPLC: RT=7.07 min, 96% (colonne XBridge)

¹H NMR, dmso-d₆, δ (ppm): 2.68 (s, 3H); 7.44 (t, 1H); 7.53 (t, 2H);7.69-7.76 (m, 3H); 7.97-8.04 (m, 5H); 8.21 (broad s, 1H); 8.31 (s, 1H);15.36 (broad s, 1H, exch).

Mass spectrum (ESI−): m/z 390 (M-H⁻, 100%).

EXAMPLES 154 TO 169

The compounds 154 to 169 were synthesized from the compound 142 and fromvarious boronic acids according to the same method described forpreparing the compound 153.

M − H⁻ Ex.* R Name of the compounds HPLC** Yld. (MH⁺) 154

(2′-Fluoro-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.80′ 95.9% 27% 404 155

(3′-Fluoro-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.93′ 98.2% 66% 408 156

(4′-Fluoro-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.92′ 98.7% 64% 408 157

(2′-Choro-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.99′ 94.8% 11% (426)158

(3′-Choro-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 7.19′ 98% 58% (426) 159

(4′-Choro-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 7.22′ 97.9% 67% (426)160

(2′-Methyl-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 7.08′ 98.4% 61% 404 161

(3′-Methyl-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 7.15′ 99.6% 60% 404 162

(4′-Methyl-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 7.16′ 99.5% 70% 404 163

(2′-Methoxy-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.85′ 100% 69% 420 164

(3′-Methoxy-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.86′ 98.5% 53% 420 165

(4′-Methoxy-biphenyl-3-yl)-(4- hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin- 3-yl)-methanone 6.83′ 99.5% 72% 420 166

(4-Hydroxy-2-methyl-1,1-dioxo- 1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3′- trifluoromethyl-biphenyl-3-yl)-methanone 7.17′ 97.5% 45% 458 167

(4-Hydroxy-2-methyl-1,1-dioxo- 1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4′- trifluoromethyl-biphenyl-3-yl)-methanone 7.22′ 98.3% 44% 458 168

3′-(4-Hydroxy-2-methyl-1,1-dioxo- 1,2-dihydro-2H-benzo[e][1,2]thiazine-3- carbonyl)-biphenyl-3-carbonitrile 6.57′ 99.5%50% 415 169

3′-(4-Hydroxy-2-methyl-1,1-dioxo- 1,2-dihydro-2H-benzo[e][1,2]thiazine-3- carbonyl)-biphenyl-4-carbonitrile 6.57′ 97.1%61% 415 *¹H NMR, dmso-d₆, Ex. 154: 2.68 (s, 3 H); 7.35-7.41 (m, 2 H);7.47-7.52 (m, 1 H); 7.62 (t, 1 H); 7.75 (t, 1 H); 7.89 (d, 1 H);7.99-8.01 (m, 3 H); 8.08 (d, 1 H); 8.21-8.22 (m, 1 H); 8.26 (s, 1 H);15.41 (broad s, exch, 1 H). Ex. 155: 2.67 (s, 3 H); 7.28 (t, 1 H);7.55-7.61 (m, 3 H); 7.74 (t, 1 H); 8.00-8.06 (m, 5 H); 8.21-8.23 (m, 1H); 8.32 (s, 1 H); 15.26 (broad s, exch, 1 H). Ex. 156: 2.67 (s, 3 H);7.37 (t, 2 H); 7.72 (t, 1 H); 7.77-7.80 (m, 2 H); 7.99-8.05 (m, 5 H);8.20-8.23 (m, 1 H); 8.27 (s, 1 H); 15.32 (broad s, exch, 1 H). Ex.157:2.68 (s, 3 H); 7.45-7.50 (m, 3 H); 7.63-7.65 (m, 1 H); 7.71-7.74 (m, 2H); 7.97-7.99 (m, 3 H); 8.03 (d,1 H); 8.15 (s, 1 H); 8.19-8.20 (m, 1 H);15.41 (broad s, exch, 1 H). Ex. 158: 2.67 (s, 3 H); 7.51 (d, 1 H); 7.57(t, 1 H); 7.72-7.76 (m, 2 H); 7.81 (d, 1 H); 7.98-8.07 (m, 5 H);8.21-8.23 (m, 1 H); 8.31 (s, 1 H); 15.26 (broad s, exch, 1 H). Ex. 159:2.67 (s, 3 H); 7.59 (d, 2 H); 7.72-7.78 (m, 3 H); 7.99-8.02 (m, 4 H);8.06 (d, 1 H); 8.20-8.23 (m, 1 H); 8.28 (s, 1 H); 15.30 (broad s, exch,1 H). Ex. 160: 2.32 (s, 3 H); 2.68 (s, 3 H); 7.27-7.38 (m, 4 H);7.67-7.73 (m, 2 H); 7.98-8.04 (m, 5 H); 8.20-8.22 (m, 1 H); 15.45 (broads, exch, 1 H). Ex. 161: 2.41 (s, 3 H); 2.67 (s, 3 H); 7.25 (d, 1 H);7.41 (t, 1 H); 7.53 (d, 1 H); 7.56 (s, 1 H); 7.71 (t, 1 H); 7.98-8.03(m, 5 H); 8.21-8.23 (m, 1 H); 8.32 (s, 1 H); 15.35 (broad s, 1 H, exch).Ex. 162: 2.37 (s, 3 H); 2.67 (s, 3 H); 7.34 (d, 2 H); 7.63 (d, 2 H);7.70 (t, 1 H); 7.97-8.01 (m, 5 H); 8.20-8.21 (m, 1 H); 8.30 (s, 1 H);15.37 (broad s, 1 H, exch). Ex. 163: 2.70 (s, 3 H); 3.83 (s, 3 H); 7.09(t, 1 H); 7.18 (d, 1 H); 7.35-7.44 (m, 2 H); 7.67 (t, 1 H); 7.79 (d, 1H); 7.97-8.01 (m, 4 H); 8.19-8.23 (m, 1 H); 8.29 (s, 1 H); 15.58 (broads, 1 H, exch). Ex. 164: 2.68 (s, 3 H); 3.86 (s, 3 H); 7.00 (dd, 1 H);7.27 (s, 1 H); 7.31 (d, 1 H); 7.44 (t, 1 H); 7.72 (t, 1 H); 7.98-8.03(m, 5 H); 8.19-8.24 (m, 1 H); 8.37 (s, 1 H); 15.32 (broad s, 1 H, exch).Ex. 165: 2.67 (s, 3 H); 3.82 (s, 3 H); 7.09 (d, 2 H); 7.66-7.71 (m, 3H); 7.94-8.02 (m, 5 H); 8.19-8.23 (m, 1 H); 8.28 (s, 1 H); 15.38 (broads, 1 H, exch). Ex. 166: 2.66 (s, 3 H); 7.74-7.83 (m, 3 H); 7.97-8.12 (m,7 H); 8.19-8.24 (m, 1 H); 8.37 (s, 1 H); 15.22 (broad s, 1 H, exch). Ex.167: 2.68 (s, 3 H); 7.78 (t, 1 H); 7.89 (d, 2 H); 7.95-8.02 (m, 5 H);8.08-8.13 (m, 2 H); 8.19-8.24 (m, 1 H); 8.34 (s, 1 H); 15.27 (broad s, 1H, exch). Ex. 168: 2.67 (s, 3 H); 7.73 (d, 1 H); 7.78 (d, 1 H); 7.91 (d,1 H); 8.00 (broad s, 3 H); 8.07-8.10 (m, 3 H); 8.19-8.25 (m, 2 H); 8.32(s, 1 H); 15.23 (broad s, 1 H, exch). Ex. 169: 2.67 (s, 3 H); 7.78 (t, 1H); 7.94-8.03 (m, 7 H); 8.08-8.12 (m, 2 H); 8.19-8.23 (m, 1 H); 8.33 (s,1 H); 15.23 (broad s, 1 H, exch). ** XBridge column.

EXAMPLE 170(4-Hydroxy-7-methanesulfonyl-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

EXAMPLE 170(4-Hydroxy-7-methanesulfonyl-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone

The compound 170 was synthesized from5-methanesulfonyl-2-methyl-benzenesulfonyl chloride according to thesame sequence of steps described for preparing the compound 17, with anoverall yield of 7%.

HPLC: RT=5.43 min, 97%

¹H NMR, dmso-d₆, δ (ppm): 2.71 (s, 3H); 3.47 (s, 3H); 7.67 (t, 1H); 7.73(t, 1H); 8.05-8.15 (m, 4H); 7.42-8.49 (m, 3H); 8.67 (s, 1H); 14.76 (se,1H, exch).

Mass spectrum (ESI+): m/z 444 (MH+, 100%).

EXAMPLE 171(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-phenyl-cyclopropyl)-methanone

EXAMPLE 171A 1-(1-Phenyl-cyclopropyl)-ethanone

The compound 171A was synthesized from 1-phenyl-cyclopropanecarbonitrileaccording to the same procedure described for preparing the compound147B, with a yield of 40%.

HPLC: RT=4.30 min, 96% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 1.15 (dd, 2H); 1.47 (dd, 1H); 1.92 (s, 3H);7.23-7.40 (m, 5H).

Mass spectrum (ESI+): m/z 161 (MH⁺, 100%).

EXAMPLE 171(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-phenyl-cyclopropyl)-methanone

The compound 171 was synthesized from the compound 171A according to thesame sequence of steps described for preparing the compound 144, with anoverall yield of 6%.

HPLC: RT=6.40 min, 96% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 1.38-1.41 (m, 2H); 1.65-1.68 (m, 2H); 2.46 (s,3H); 7.25-7.37 (m, 5H); 7.78-7.83 (m, 1H); 7.86-7.91 (m, 2H); 8.06-8.08(m, 1H), 15.31 (s, 1H, exch).

Mass spectrum (ESI+): m/z 356 (MH⁺, 100%).

EXAMPLE 1721-[3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-phenyl]-ethanone

EXAMPLE 1721-[3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-phenyl]-ethanone

The compound 172 was synthesized from 1-(3-acetyl-phenyl)-ethanoneaccording to the same sequence of steps described for preparing thecompound 144, with an overall yield of 21%.

HPLC: RT=6.25 min, 97% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 2.64 (s, 3H); 2.66 (s, 3H); 7.79 (t, 1H); 8.00(broad s, 3H); 8.15-8.35 (m, 3H); 8.58 (s, 1H); 15.21 (broad s, 1H,exch).

Mass spectrum (ESI−): m/z 356 (M-H⁻, 100%).

EXAMPLE 173(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-methanone

EXAMPLE 173A1-[3-(2,2,2-Trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethanone

1-(3-acetyl-phenyl)-ethanone (2.5 g, 15.4 mmol) is dissolved in 120 mLof THF under a nitrogen atmosphere and at 0° C. in the presence ofTMS-CF₃ (2.7 mL, 18.4 mmol). TBAF (1M/THF, 18.4 mL, 18.4 mmol) is addedwithin 20 minutes by means of a syringe pump. The cold bath is removedand the reaction medium is stirred for a further 18 hours and thenneutralized by adding a saturated NaHCO₃ solution, and finally extracted3 times with ethyl acetate. The organic phases are combined, washed withwater and then dried on magnesium sulfate, filtered and concentratedunder reduced pressure. The thereby obtained residue is purified onsilica (gradient of 0% to 50% ethyl acetate in heptane in 20 min), inorder to obtain the partly purified compound 173A (2.87 g). It is usedas such in the next step.

EXAMPLE 173B2-Bromo-1-[3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethanone

The compound 173B was synthesized from the compound 173A according tothe procedure for preparing the compound 144A, with a yield of 57%.

HPLC: RT=5.50 min, 74% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 1.73 (s, 3H); 4.96 (s, 2H); 6.81 (broad s, 1H,exch); 7.60 (t, 1H); 7.89 (d, 1H); 8.03 (d, 1H); 8.17 (s, 1H).

EXAMPLE 173(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-methanone

The compound 173 was synthesized from saccharin and from the compound173B according to the same sequence of steps described for preparing thecompound 1, with an overall yield of 52%.

HPLC: RT=6.05 min, 95% (XBridge column)

¹H NMR, dmso-d₆, (ppm): 1.76 (s, 3H); 2.61 (s, 3H); 6.84 (s, 1H, exch);7.67 (t, 1H); 7.90-8.05 (m, 5H); 8.17-8.23 (m, 1H); 8.36 (s, 1H); 15.47(broad s, 1H, exch).

Mass spectrum (ESI+): m/z 445 (MNH₄ ⁺, 100%).

EXAMPLE 174(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-methanone

EXAMPLE 174A1-[3-(2,2,2-Trifluoro-1-trimethylsilanyloxy-ethyl)-phenyl]-ethanone

3-acetylbenzaldehyde (1.27 g, 8.57 mmol) is dissolved in 30 mL of DMFunder a nitrogen atmosphere in the presence of potassium carbonate (59mg, 0.42 mmol) and of TMS-CF₃ (1.52 mL, 10.3 mmol). The reaction mixtureis stirred for 30 minutes at room temperature and then neutralized with1 mL of a saturated NH₄Cl solution and concentrated under reducedpressure. The residue is taken up in ethyl acetate and then washed oncewith HCl (1N in water), dried on magnesium sulfate, filtered andconcentrated under reduced pressure in order to obtain the partlypurified compound 174A (2.55 g). It is used as such in the next step.

HPLC: RT=5.15 min, 42% (OH) et 6.91 min, 40% (OTMS) (XBridge column,partial deprotection on the column).

¹H NMR, dmso-d₆, δ (ppm): 0.09 (s, 9H); 2.60 (s, 3H); 5.60 (q, 1H); 7.60(t, 1H); 7.76 (d, 1H); 8.02 (d, 1H); 8.08 (s, 1H).

Mass spectrum (ESI+): m/z 291 (MH⁺, 100%).

EXAMPLE 174B2-Bromo-1-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-ethanone

The compound 174B was synthesized from the compound 174A according tothe procedure for preparing the compound 144A, with a yield of 60%.

HPLC: RT=5.23 min, 83% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 4.93 (s, 2H); 5.32 (q, 1H); 7.03 (broad s, 1H,exch); 7.61 (t, 1H); 7.81 (d, 1H); 8.05 (d, 1H); 8.11 (s, 1H).

EXAMPLE 174(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-methanone

The compound 174 was synthesized from saccharin and from the compound174B according to the same sequence of steps described for preparing thecompound 1, with an overall yield of 33%.

HPLC: RT=5.92 min, 92% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 2.60 (s, 3H); 5.32 (broad s, 1H); 7.05 (d, 1H,exch); 7.67 (t, 1H); 7.80 (d, 1H); 7.98 (broad s, 3H); 8.08 (d, 1H);8.20 (broad s, 2H); 15.45 (broad s, 1H, exch).

Mass spectrum (ESI+): m/z 431 (MNH₄ ⁺, 100%).

EXAMPLE 1753-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzoicacid

EXAMPLE 1753-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzoicacid

The compound 143 (100 mg, 0.29 mmol) is dissolved in 1 mL of KOH (30% inwater) in the presence of 330 μl of ethanol, and then heated to 70° C.for 18 hours. The reaction medium is diluted with 10 mL of water, washedtwice with ether, brought back to pH=2 with an HCl (6N in water) andfinally extracted three times with a solution of 20% methanol in DCM.The organic phases are combined, dried on magnesium sulfate, filteredand concentrated in order to obtain the compound 175 as a yellow solid(99 mg, 93%).

HPLC: RT=5.49 min, 98% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 2.64 (s, 3H); 7.77 (t, 1H); 7.99-8.00 (m, 3H);8.20-8.24 (m, 2H); 8.28 (d, 1H); 8.61 (s, 1H); 13.33 (s, exch, 1H);15.32 (s, exch, 1H).

Mass spectrum (ESI−): m/z 358 (M-H⁻, 100%).

EXAMPLE 1763-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2,1-benzo[e][1,2]thiazine-3-carbonyl)-N-methyl-benzamide

EXAMPLE 1763-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N-methyl-benzamide

The compound 175 (150 mg, 0.41 mmol) is dissolved in 3 mL of DMF underan inert atmosphere in the presence of(3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (120 mg, 0.62mmol), of 3-hydroxy-3H-benzo[d][1,2,3]triazin-4-one (102 mg, 0.62 mmol)and iPr₂NEt (162 mg, 1.25 mmol), and then stirred at room temperaturefor 72 hours. The reaction mixture is concentrated under reducedpressure, diluted with 20 mL of DCM and washed twice with HCl (1N inwater). The aqueous phases are collected and extracted DCM. The organicphases are combined, dried on magnesium sulfate, filtered andconcentrated. The thereby obtained residue is purified on a column of 12g of silica (12 mL/min, gradient of 0% to 25% acetone in DCM in 20minutes), in order to obtain the compound 176 as a yellow solid (101 mg,64%).

HPLC: RT=5.21 min, 97% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 2.63 (s, 3H); 2.82 (d, 3H); 7.72 (t, 1H), 7.99(d, 3H); 8.10 (d, 1H); 8.20-8.22 (m, 2H); 8.42 (s, 1H); 8.66 (d, 1H);15.35 (broad s, 1H, exch).

Mass spectrum (ESI+): m/z 373 (MH⁺, 100%).

EXAMPLES 177 TO 183

The compounds 177 to 183 were synthesized from the compound 175 and fromvarious amines according to the same procedure described for preparingthe compound 176.

Ex.* R Name of the compounds HPLC** Yld. MH⁺ 177

3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N,N-dimethyl-benzamide 5.33′ 95.8% 44% 387 178

N-Ethyl-3-(4-hydroxy-2-methyl-1,1- dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide 5.41′ 96.9% 39% 387 179

3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N,N-diethyl-benzamide 5.71′ 96.9% 34% 415 180

N-Cyclopropyl-3-(4-hydroxy-2-methyl- 1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide 5.43′ 96.6% 33% 399 181

N-Cyclopropylmethyl-3-(4-hydroxy-2- methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)- benzamide 5.71′ 98.7% 33% 413 182

3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2- dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N-phenyl-benzamide 6.09′ 99.5% 67% 435 183

N-Benzyl-3-(4-hydroxy-2-methyl-1,1- dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide 5.96′ 93.8%  6% 449 *¹H NMR, dmso-d₆, Ex.177: 2.65 (s, 3 H); 2.98 (s, 3 H); 3.03 (s, 3 H); 7.68-7.75 (m, 2 H);7.99-8.07 (m, 4 H); 8.08 (d, 1 H); 8.20-8.21 (d, 1 H); 15.28 (broad s,exch, 1 H). Ex. 178: 1.15 (t, 3 H); 2.63 (s, 3 H); 3.29-3.36 (m, 2 H +H₂O); 7.71 (t, 1 H); 7.99-8.00 (m, 3 H); 8.12 (d, 1 H); 8.21-8.22 (m, 2H); 8.42 (s, 1 H); 8.68 (t, 1 H); 15.36 (broad s, exch, 1 H). Ex. 179:1.09-1.23 (m, 6 H); 2.64 (s, 3 H); 3.24-3.47 (m, 4 H + H₂O); 7.66-7.72(m, 2 H); 7.95-8.08 (m, 5 H); 8.20-8.21 (m, 1 H); 15.28 (broad s, exch,1 H). Ex. 180: 0.71-0.75 (m, 2 H); 0.8 (m, 2 H); 2.63 (s, 3 H);2.86-2.91 (m, 1 H); 7.70 (t, 1 H); 7.99-8.00 (m, 3 H); 8.09 (d, 1 H);8.20-5.21 (m, 2 H); 8.40 s (1 H); 8.66 (d, 1 H); 15.34 (broad s, exch, 1H). Ex. 181: 0.45-0.47 (m, 2 H); 0.6 (m, 2 H); 1.06 (m, 1 H); 2.64 (s, 3H); 3.18 (t, 2 H); 7.72 (t, 1 H); 7.99-8.00 (m, 3 H); 8.13 (d, 1 H);8.21 (m, 2 H); 8.43 (s, 1 H); 8.78 (t, 1 H); 15.35 (broad s, exch, 1 H).Ex. 182: 2.66 (s, 3 H); 7.13 (t, 1 H); 7.38 (t, 2 H); 7.78-7.81 (m, 3H), 8.00 (d, 3 H); 8.21-8.28 (m, 3 H); 8.52 (s, 1 H); 10.47 (s, 1 H);15.33 (broad s, exch, 1 H). Ex. 183: 2.63 (s, 3 H); 4.52 (d, 2 H);7.25-7.28 (m, 1 H); 7.32-7.36 (m, 4 H); 7.73 (t, 1 H); 8.00 (d, 3 H);8.17-8.25 (m, 3 H); 8.49 (s, 1 H); 9.26-9.27 (m, 1 H); 15.34 ( broad s,exch, 1 H). ** XBridge column.

EXAMPLE 1843-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide

EXAMPLE 1843-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide

The compound 175 (150 mg, 0.42 mmol) is dissolved in 3 mL of THF in thepresence of PyBOP (239 mg, 0.46 mmol), of ammonia (152 μl, 1.25 mmol)and of DIEA (80 μl, 0.46 mmol) and stirred at room temperature for 4hours. The reaction medium is diluted with 20 mL of DCM and washed withHCl (1N in water). The aqueous phase is extracted four times with DCM.The organic phases are combined, dried on magnesium sulfate, filteredand concentrated in order to obtain the compound 184 as a yellow solid(71 mg, 46%).

HPLC: RT=5.06 min, 97.4% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 2.63 (s, 3H); 7.57 (s, 1H); 7.71 (t, 1H); 7.99(d, 3H); 8.14-8.23 (m, 4H); 8.46 (s, 1H); 15.36 (broad s, exch, 1H).

Mass spectrum (ESI+): m/z 359 (MH⁺, 100%).

EXAMPLE 1853-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzoicacid ethyl ester

EXAMPLE 1853-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzoicacid ethyl ester

The compound 175 (150 mg, 0.42 mmol) is dissolved in 6 mL ethanol in thepresence of pTsOH (8 mg, 0.04 mmol), and refluxed with stirring for 18hours. The reaction medium is concentrated under reduced pressure. Thethereby obtained residue is purified on a column of 12 g of silica (12mL/min, DCM), in order to obtain the compound 185 as a yellow solid (138mg, 84%).

HPLC: RT=6.28 min, 95.8% (XBridge column)

¹H NMR, dmso-d₆, δ (ppm): 1.36 (t, 3H); 2.64 (s, 3H); 4.37 (q, 2H); 7.79(t, 1H); 8.00 (d, 3H); 8.20-8.30 (m, 3H); 8.65 (s, 1H), 15.23 (broad s,exch, 1H).

Mass spectrum (ESI+): m/z 405 (MH⁺, 100%).

EXAMPLE 186(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-3-yl-phenyl)-methanone

EXAMPLE 186(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-3-yl-phenyl)-methanone

The compound 142 (200 mg, 0.5 mmol) is dissolved under an inertatmosphere in 1.5 mL of 1,4-dioxane in the presence ofpyridin-3-ylboronic acid (104 mg, 0.76 mmol), of tripotassiumorthophosphate (1.27 mol/l, 679 μl, 0.86 mmol), oftris(dibenzylideneacetone)dipalladium (23 mg, 0.025 mmol) and oftricyclo-hexylphosphine (21 mg, 0.076 mmol). The reaction medium isheated to 100° C. for 18 hours and then brought back to roomtemperature, diluted with DCM and washed with a saturated NH₄Clsolution. The organic phase is dried on magnesium sulfate, filtered andconcentrated under reduced pressure. The thereby obtained residue ispurified on a column of 12 g of silica (16 mL/min, gradient of 0% to 5%methanol in 7 min), in order to obtain the compound 186 (128 mg, 62%).

HPLC: RT=5.07 min, 97.5% (XBridge column)

¹H NMR, dmso-d₆, (ppm): 2.67 (s, 3H); 7.77-7.82 (m, 3H); 7.98-8.01 (m,3H); 8.11-8.15 (m, 2H); 8.22 (dd, 1H); 8.39 (s, 1H); 8.71 (d, 2H); 15.20(broad s, 1H, exch).

Mass spectrum (ESI+): m/z 393 (MH⁺, 100%).

EXAMPLES 187 TO 195

The compounds 187 to 195 were synthesized from the compound 144 and fromvarious boronic acids according to the same method as described forpreparing the compound 186.

M − H− Ex.* R Name of the compounds HPLC** Yld. (MH⁺) 187

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin- 4-yl-phenyl)-methanone 5.02′97.5% 62% 393 188

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methyl-pyridin-3-yl)-phenyl]-methanone 5.04′ 93% 49% 407 189

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(5-methyl-pyridin-3-yl)-phenyl]-methanone 5.09′ 97.9% 53% 407 190

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methyl-pyridin-3-yl)-phenyl]-methanone 5.05′ 98.1% 60% 407 191

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methyl-pyridin-3-yl)-phenyl]-methanone 5.02′ 100% 70% 407 192

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methoxy-pyridin-3-yl)-phenyl]-methanone 5.07′ 100% 21% 423 193

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-fluoro-pyridin-3-yl)-phenyl]-methanone 6.28′ 97.3% 37% 411 194

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methoxy-pyridin-3-yl)-phenyl]-methanone 6.41′ 96.9% 63% 423 195

(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methoxy-pyridin-3-yl)-phenyl]-methanone 6.35′ 97.5% 27% 423 *¹H NMR, dmso-d₆,Ex. 187: 2.67 (s, 3 H); 7.77-7.82 (m, 3 H); 7.98-8.01 (m, 3 H);8.11-8.15 (m, 2 H); 8.22 (dd, 1 H); 8.39 (s, 1 H); 8.71 (d, 2 H); 15.20(broad s, 1 H, exch). Ex. 188: 2.54 (s, 3 H); 2.67 (s, 3 H); 7.41 (d, 1H); 7.75 (t, 1 H); 7.98-8.07 (m, 6 H); 8.19-8.23 (m, 1 H); 8.31 (s, 1H); 8.82 (s, 1 H); 15.28 (broad s, 1 H, exch). Ex. 189: 2.40 (s, 3 H);2.97 (s, 3 H); 7.76 (t, 1 H); 7.98-8.09 (m, 6 H); 8.19-8.24 (m, 1 H);8.32 (s, 1 H); 8.48 (s, 1 H); 8.76 (s, 1 H); 15.25 (broad s, 1 H, exch).Ex. 190: 2.35 (s, 3 H); 2.68 (s, 3 H); 7.42 (d, 1 H); 7.76 (d, 2 H);7.97-8.07 (m, 5 H); 8.19-8.23 (m, 1 H); 8.46 (s, 1 H); 8.49 (d, 1 H);15.35 (broad s, 1 H, exch). Ex. 191: (CDCl₃) 2.58 (s, 3 H); 2.74 (s, 3H); 7.24 (dd, 1 H); 7.51-7.64 (m, 3 H); 7.78-7.84 (m, 2 H); 7.91-7.96(m, 1 H); 8.10 (s, 1 H); 8.19-8.23 (m, 2 H); 8.56 (dd, 1 H); 15.75 (s, 1H, exch). Ex. 192: 2.70 (s, 3 H); 3.93 (s, 3 H); 7.24 (d, 1 H); 7.69 (t,1 H); 7.82 (d, 1 H); 7.96-8.00 (m, 4 H); 8.17-8.21 (m, 1 H); 8.27 (s, 1H); 8.45 (s, 1 H); 8.51 (d, 1 H); 15.48 (broad s, 1 H, exch). Ex. 193:2.67 (s, 3 H); 7.37 (dd, 1 H); 7.77 (t, 1 H); 8.00 (broad s, 3 H);8.04-8.11 (m, 2 H); 8.19-8.23 (m, 1 H); 8.29 (s, 1 H); 8.32-8.39 (td, 1H); 8.32 (s, 1 H); 15.24 (broad s, 1 H, exch). Ex. 194: 2.70 (s, 3 H);3.95 (s, 3 H); 7.16 (dd, 1 H); 7.70 (t, 1 H); 7.82-7.89 (m, 2 H);7.98-8.03 (m, 4 H); 8.17-8.24 (m, 2 H); 8.37 (s, 1 H); 15.53 (broad s, 1H, exch). Ex. 195: 2.67 (s, 3 H); 3.92 (s, 3 H); 6.98 (d, 1 H); 7.73 (t,1 H); 7.99-8.05 (m, 5 H); 8.09 (dd, 1 H); 8.21 (broad s, 1 H); 8.28 (s,1 H); 8.55 (s, 1 H); 15.30 (broad s, 1 H, exch). **XBridge column.

EXAMPLES 196 AND 197

The compounds 196 and 197 were synthesized from saccharin and from2-bromo-1-(3-chlorophenyl)ethanone and2-bromo-1-(3-fluorophenyl)ethanone respectively according to the samemethod described for preparing the compound 1.

Ex.* R Name of the compounds HPLC** Yld.¹ M-H⁻ 196 Cl(3-Chloro-phenyl)-(4-hydroxy-2-   6.43′ 37% 348/350methyl-1,1-dioxo-1,2-dihydro-2H- 98.7%benzo[e][1,2]thiazin-3-yl)-methanone 197 F(3-Fluoro-phenyl)-(4-hydroxy-2-   6.14′ 19% 332methyl-1,1-dioxo-1,2-dihydro-2H- 96.5%benzo[e][1,2]thiazin-3-yl)-methanone ¹Overall yield for the 3 steps. *¹H NMR, dmso-d₆, Ex. 196: 2.66 (s, 3H); 7.67 (t, 1H); 7.78 (d, 1H); 7.99(s, 5H); 8.15 (broad s, 1H); 15.07 (broad s, 1H, exch.). Ex. 197: 2.65(s, 3H); 7.58 (t, 1H); 7.70 (dd, 1H); 7.76 (d, 1H); 7.90 (d, 1H); 7.99(broad s, 3H); 8.20 (broad s, 1H); 15.15 (broad s, 1H, exch.). **XBridge column.

The derivatives of the present invention are selective inhibitors of11-HSD1 relatively to 11-HSD2 as shown by the results of the modelsdescribed below:

1) Human Enzymatic Activity of 11β-HSD1 from Liver Microsomes afterTreatment with Inhibitor Compounds (Inhibition %).

The enzymatic test is based on the conversion of cortisone into cortisolby 11β-HSD1. The enzymatic reaction is started by adding 1 μg of humanhepatic microsome (Xenotech) to wells (half volume 96-well plates,reaction volume of 50 μL) containing 160 nM of cortisone in a Tris 20 mMbuffer (pH 7.4) with 5 mM EDTA, 200 μM NADPH and the inhibitor compoundor the carrier (1% DMSO). A calibration curve of known cortisolconcentrations is produced simultaneously under the same experimentalconditions. The plates are incubated for 2 hours at 37° C. (enzymaticphase). By adding 25 μL of conjugate cortisol-d2 and of 25 μL ofanti-cortisol anαtibody labeled with Eu³⁺ cryptate per well, theenzymatic reaction may be stopped and after incubation of 2 hours atroom temperature the formed cortisol (detection phase) may be quantifiedby HTRF® (CIS bio international, reference 62CO2PEC). The fluorescencemeasurements are conducted with a Fusion™ α(Perkin Elmer) reader. Foreach well, fluorescence is measured at 620 nm and at 665 nm. A ratio(λ665 nm/λ620 nm) and a specific FRET signal are calculated, with whichan inhibition percentage may be determined for each concentration ofevaluated inhibitor compound.

REFERENCES Posters

IC₅₀ determination of Carbenoxolone and Glycyrrhetinic acid on 11-betahydroxysteroid dehydrogenase type 1 activity by HTRF®: C. Tokuda et al.,Screentech, March 2004, San Diego (USA).New Cortisol assay for 11-beta hydroxysteroid dehydrogenase type 1activity using a new HTRF® acceptor, d2: M. Amoravain et al., SBS,12^(th) Annual Conference, September 2006, Seattle (USA).

2) Human Enzymatic Activity of 11β-HSD1 from Liver Microsomes afterTreatment with Inhibitor Compounds (Inhibition % or EC₅₀).

The enzymatic test is based on the conversion of [³H] cortisone into[³H] cortisol by 11β-HSD1. The enzymatic reaction is stated by adding 1μg (standardization of this amount in order to obtain 80% of thesubstrate conversion maximum under the experimental conditions) of humanhepatic microsomes (Xenotech) to wells (Optiplate™ 96-well plates,reaction volume of 50 μL) containing 20 nM of [1,2-³H] cortisone(specific activity of 40-50 Ci/mmol, Amersham-GE Healthcare) in a 50 mMHEPES buffer at (pH 7.4) with 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 1 mMNADPH and the inhibitor compound or the carrier (1% DMSO). The sealedplates are centrifuged at low speed for mixing the components and thenincubated for 2 hours at 37° C. (enzymatic phase). The enzymaticreaction is stopped by adding 70 μl/well of complex [10 mg/mL of yttriumsilicate SPA beads associated with the protein A (GE Healthcare) andpre-incubated with an anti-cortisol monoclonal antibody (East CoastBiologics, ME)] containing 10 μM of 18β-glycerrhitinic acid. The platesare sealed and then incubated under slow orbital stirring for 2 hours atroom temperature (detection phase). After centrifugation, measurementsare conducted with a scintillation counter (TopCount NXT (Perkin Elmer).A percentage of inhibition for each evaluated compound concentration iscalculated relatively to the standard enzymatic activity (carrier 1%DMSO) with which the potential of each compound may then be determined(EC₅₀ obtained by the software SigmaPlot v.11, a logistic equation with4 parameters).

REFERENCES

-   Development and application of a scintillation proximity assay (SPA)    for identification of selective inhibitors of 1β-hydroxysteroid    dehydrogenase type 1: S. Mundt et al., ASSAY and Drug Development    Technologies, volume 3, number 4, 367-375, 2005.-   High-throughput screening of 11β-hydroxysteroid dehydrogenase type 1    in scintillation proximity assay format: K. Solly et al., ASSAY and    Drug Development Technologies, volume 3, number 4, 377-384, 2005.

3) Human Enzymatic Activity of 11β-HSD2 from Kidney Microsomes afterTreatment with the Inhibitor Compounds (Inhibition %).

The enzymatic test is based on the conversion of [³H] cortisol into [³H]cortisone by 11β-HSD2. The enzymatic reaction is started by adding 0.75μg (standardization of this amount in order to obtain 80% of theconversion maximum of the substrate under the experimental conditions)of human kidney microsomes (Xenotech) to wells (Optiplate™ 96-wellplates, a reaction volume of 50 μL) containing 8 nM [1,2,6,7-³H]cortisol (specific activity of 70-75 Ci/mmol, Amersham-GE Healthcare) ina 50 mM HEPES buffer (pH 7.4) with 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 1mM NAD⁺ and the inhibitor compound or the carrier (1% DMSO). The sealedplates are centrifuged at low speed in order to mix the components andthen incubated for 2 hours at 37° C. (enzymatic phase). The enzymaticreaction is stopped by adding 70 μl/well of complex [10 mg/mL of yttriumsilicate SPA beads associated with protein A (GE Healthcare) andpre-incubated with an anti-cortisol monoclonal antibody (East CoastBiologics, ME)] containing 10 μM of 18β-glycerrhitinic acid. The platesare sealed and then incubated under slow orbital stirring for 2 hours atroom temperature (detection phase). After centrifugation, themeasurements are conducted with a scintillation counter TopCount NXT(Perkin Elmer). An inhibition percentage for each evaluated compoundconcentration is calculated relatively to the standard enzymaticactivity (carrier 1% DMSO).

REFERENCES

-   Development and application of a scintillation proximity assay (SPA)    for identification of selective inhibitors of 11β-hydroxysteroid    dehydrogenase type 1: S. Mundt et al., ASSAY and Drug Development    Technologies, volume 3, number 4, 367-375, 2005.-   High-throughput screening of 11β-hydroxysteroid dehydrogenase type 1    in scintillation proximity assay format: K. Solly et al., ASSAY and    Drug Development Technologies, volume 3, number 4, 377-384, 2005.

Results:

The few examples which follow, selected from compounds of the presentinvention, illustrate the quite unexpected capability of these compoundsof selectively inhibiting 11β-HSD1 relatively to 11β-HSD2:

11β-HSD1/HTRF 11β-HSD1/SPA 11β-HSD2/SPA % inhib. % inhib. % inhib.Exemples (10⁻⁶M) (10⁻⁶M) EC₅₀ (nM) (10⁻⁵M) 1 99 97 16 42 3 99 93 64 33 998 88 60 5 17 100 99 11 61 18 100 91 69 25 46 100 91 72 63 54 100 97 2771 123 100 93 43 31 142 100 87 21 — 192 100 98 17 —

The object of the present invention is the compounds of general formula(I) or one of their stereoisomers or one of their salts acceptable forpharmaceutical use, for their use as a drug.

The object of the present invention is also the pharmaceuticalcompositions containing as an active ingredient a compound of generalformula (I) or one of its stereoisomers, or one of its salts acceptablefor pharmaceutical use in association with a pharmaceutically acceptablecarrier, as drugs. These compositions may for example assume the form ofsolid, liquid compositions, emulsions, lotions or creams.

These pharmaceutical compositions containing as an active ingredient acompound of general formula (I) or one of their stereoisomers or one oftheir salts acceptable for pharmaceutical use may be used for inhibiting11β-hydroxysteroid dehydrogenase type 1 (11βHSD1).

These pharmaceutical compositions containing as an active ingredient acompound of general formula (I) or one of its stereoisomers or one ofits salts acceptable for pharmaceutical use for both curative andpreventive treatment of diabetes of type 2.

These pharmaceutical compositions containing as an active ingredient acompound of general formula (I) or one of its stereoisomers or one ofits salts acceptable for pharmaceutical use for both curative andpreventive treatment of disorders related to the type 111β-hydroxysteroid dehydrogenase (11βHSD1); or obesity; ordyslipidemias; or arterial hypertension; or atherosclerosis and clinicalpathologies which result therefrom such as coronary strokes, orcerebro-vascular strokes, or arteritis of the lower limbs; orhyperglycemias; of intolerance to glucose; or insulin-resistance; orhypertriglyceridemias; or hypercholesterolemias; or restenoses, orpancreatitises; or retinopathies; or nephropathies; or neuropathies; orcertain types of cancer or glaucomas.

These compositions may be administered in association with ananti-diabetic such as biguanides (for example metformine), various formsof insulin, sulfonylureas (for example carbutamide, glibornuride,glipizide, gliclazide, glibenclamide, glimepiride), meglitinides (forexample nateglinide, repaglinide, mitiglinide), PPAR modulators (forexample pioglitazone), inhibitors of alpha-glucosidase (for exampleacarbose, miglitol, voglibose), GLP-1 analogs (for example exenatide,liraglutide), DPP-4 inhibitors (for example sitagliptin, vildagliptin),analogs of amyline (for example pramLintide).

These compositions may also be administered in association with ananti-obesity agent such as for example orlistat or sibutramine.

As solid compositions for oral administration, tablets, pills, powders(gelatin capsules, tablets) or granules may be used. In thesecompositions, the active ingredient according to the invention is mixedwith one or more inert diluents such as starch, cellulose, saccharose,lactose or silica, under an argon stream. These compositions may alsocomprise substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a coloring agent, acoating (dragees) or a varnish.

As liquid compositions for oral administration, pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups and elixirscontaining inert diluents such as water, ethanol, glycerol, vegetableoils or paraffin oil may be used. These compositions may comprisesubstances other than diluents, for example wetting products,sweeteners, thickeners, flavoring agents or stabilizers.

The sterile compositions for parenteral administration may preferablyaqueous or non-aqueous solutions, suspensions or emulsions. As a solventor carrier, water, propyleneglycol, polyethyleneglycol, vegetable oils,in particular olive oil, injectable organic esters for example ethyloleate or other suitable organic solvents may be used. Thesecompositions may also contain adjuvants, in particular wetting,isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization may be accomplished in several ways, for example byaseptizing filtration, by incorporating to the composition sterilizingagents, by irradiation or by heating. They may also be prepared assterile solid compositions which may be dissolved at the moment of usein sterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain in addition to the active product, excipientssuch as cocoa butter, semi-synthetic glycerides or polyethyleneglycols.

The compositions for topical administration may for example be creams,lotions, collyria, collutories, nasal drops or aerosols.

The doses depend on the sought effect, on the duration of the treatmentand on the administration route used; they are generally comprisedbetween 0.001 g and 1 g (preferably comprised between 0.005 g and 0.75g) per day preferably orally for an adult with unit doses ranging from0.1 mg to 500 mg of active substance. Generally, the physician willdetermine the suitable dosage depending on the age, the weight and allthe other factors specific to the subject to be treated.

1. Compounds fitting general formula (I):

wherein: R₁ represents: Hydrogen; C₁-C₆ alkyl; COR₅; SO₂R₅;CO(CH₂)_(m)R₆; CO(CH₂)_(m)OR₆; (CH₂)_(m)R₆; (CH₂)_(m)CONR₇R₈;(CH₂)_(n)NR₇R₈; (CH₂)_(n)OR₆; CHR₇OR₉; (CH₂)_(m)R₁₀ m represents: 1 to 6n represents: 2 to 6 R₂ represents: A phenyl substituted with one ormore groups selected from a halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃,SMe, COMe, CMe(OH)CF₃, CH(OH)CF₃, COOR₇, CONR₇R₁₁; a naphthyl,1,2,3,4-tetrahydro-naphthalene, biphenyl, phenyl, pyridine or aheterocycle different from indole in the case where R₁, R₄ and R′₄represent a hydrogen, either non-substituted or substituted with one ormore groups selected from a halogen or C₁-C₆ alkyl, CN, OH, CF₃, OCF₃,OMe, SMe; a cycloalkyl either non-substituted or substituted with OH,CONH₂, SO₂Me, SO₂NH₂; C₁-C₆ alkyl aryl or cycloalkyl aryl, Proviso:—theR₂ group is always bound to the carbonyl through a carbon atom. When R₂is a phenyl, the COOR₇ substituent is never in the position 4 relativelyto the carbonyl. R₃ represents: Methyl or ethyl R₄ and R′₄, eitheridentical or different, represent: Hydrogen; halogen; C₁-C₆ alkyl; CN;CF₃; OCF₃; SMe; OMe; NR₇R₈; SO₂Me R₅ represents: C₁-C₆ alkyl; phenyleither non-substituted or substituted with one or more groups selectedfrom halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe; a naphthyl, eithernon-substituted or substituted with one or more groups selected fromhalogen or C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe; a cycloalkyl eithernon-substituted or substituted with a CONH₂, SO₂Me, SO₂NH₂, heteroaryleither non-substituted or substituted with one or more groups selectedfrom halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe R₆ represents:Hydrogen; C₁-C₆ alkyl; phenyl either non-substituted or substituted withone or more groups selected from halogen, C₁-C₆ alkyl, CN, OH, CF₃,OCF₃, SMe; a naphthyl or heterocycle, either non-substituted orsubstituted with one or more groups selected from halogen or C₁-C₆alkyl, CN, OH, CF₃, OCF₃, SMe; a cycloalkyl either non-substituted orsubstituted with CONH₂, SO₂Me, SO₂NH₂ R₇ represents: Hydrogen, C₁-C₆alkyl R₈ represents: Hydrogen, C₁-C₆ alkyl, phenyl eithernon-substituted or substituted with one or more groups selected fromhalogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe; a naphthyl or heterocycle,either non-substituted or substituted with one or more groups selectedfrom halogen, C₁-C₆ alkyl, CN, OH, CF₃, OCF₃, SMe; a cycloalkyl eithernon-substituted or substituted with CONH₂, SO₂Me, SO₂NH₂ R₇ and R₈ takentogether may form a cycle of 4 to 6 members with the nitrogen atom towhich they are bound and which may contain one or more heteroatomsselected from N, S or O and may either be non-substituted or substitutedwith one or more groups selected from C₁-C₆ alkyl, C₁-C₆ alkyl aryl oraryl. R₉ represents: COOMe, COOEt R₁₀ represents: Halogen, COOH, COOR₇R₁₁ represents: Hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl cycloalkyl,cycloalkyl, aryl, C₁-C₆ alkyl aryl as well as their stereoisomers, saltsand solvates acceptable for therapeutic use.
 2. The compounds accordingto claim 1 characterized in that R₁ is a hydrogen.
 3. The compoundsaccording to claim 1 characterized in that OR₁ represents an ester or anether.
 4. The compounds according to any of claims 1 to 3 characterizedin that R₂ represents a naphthyl or a 1,2,3,4-tetrahydro-naphthalene ora biphenyl or a phenyl pyridine either non-substituted or substitutedwith one or more groups selected from a halogen, C₁-C₆ alkyl, CN, OH,CF₃, OCF₃, OMe, SMe; or a phenyl substituted with one or more halogens,CN, CF₃ or C₁-C₆ alkyl.
 5. The compounds according to any of claims 1 to3 characterized in that R₄ and R′₄ represent a hydrogen.
 6. A compoundaccording to claim 1, selected from:(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(adamantan-1-yl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-methylphenyl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-chlorophenyl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-cyanophenyl)methanoneBiphenyl-4-yl-(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(2,4-dichlorophenyl)methanone(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(adamantan-1-yl)methanone(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-methylphenyl)methanone(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(4-chlorophenyl)methanoneBiphenyl-4-yl-(4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)methanone(5-Chloro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(5-Chloro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(6-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(6-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(7-Fluoro-4-hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanoneBenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclohehanecarboxylic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester tertButylcarboxylic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Methylbenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chlorobenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester tertButylcarboxylic acid16-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclohexanecarboxylic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Benzoic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Methylbenzoic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester tertButylcarboxylic acid6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclohexanecarboxylic acid6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Benzoic acid6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Methylbenzoic acid6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chlorobenzoic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chlorobenzoic acid6-fluoro-2-ethyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Naphthalen-1-ylcarboxylic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Naphthalen-2-ylcarboxylic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Naphthalen-1-ylcarboxylic acid2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl esterNaphthalen-2-ylcarboxylic acid2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester4-Chlorobenzoic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chlorobenzoic acid2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester(Naphthalene-2-yloxy)acetic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester (Naphthalene-2-yloxy)acetic acid2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester(Naphthalene-1-yloxy)acetic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester (Naphthalene-1-yloxy)acetic acid2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl ester(4-Chlorophenoxy)acetic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester (4-Chlorophenoxy)acetic acid2-methyl-3-(4-cyanobenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yl esterAcetic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 2,4-Dichlorobenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Fluorobenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclopentanoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 2-Furanoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Thiophen-2-carboxylic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 3-Chlorobenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 2-Chlorobenzoic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Phenoxyacetic acid2-methyl-3-(naphthalene-2-ylcarbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester(4-Methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-Ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-Propyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-Butyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-(2-Chloroethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanone(4-[2-(Naphthalen-2-yloxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)tolyl)methanone(4-(2-Phenoxy-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanoneMethyl2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)acetate2-(2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)aceticacid2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(naphthalen-1-yl)acetamide2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(adamantan-1-yl)acetamide2-(2-Methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy)-N-(adamantan-2-yl)acetamideMethyl2-(1,1-dioxo-2-methyl-3-(4-methylbenzoyl)-2H-benzo[e][1,2]thiazin-4-yloxy)acetate(1,1-dioxo-2-methyl-3-(4-methylbenzoyl)-2H-benzo[e][1,2]thiazin-4-yloxy)aceticacid2-[2-Methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-piperidin-1-yl-ethanone2-[2-Methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazin-1-yl)-ethanone1-(4-Benzyl-piperazin-1-yl)-2-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethanone(4-Chloro-phenoxy)-acetic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester (Naphthalen-1-yloxy)-acetic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester (Naphthalen-2-yloxy)-acetic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester(4-[2-(naphthalen-1-yloxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanone(4-[2-(4-chlorophenyloxy)ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanoneAcetic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Propanoic acid2-methyl-3-(4-methylbenzoyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester(4-methyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanone(4-ethyloxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(p-tolyl)methanone[4-(2-Bromo-ethoxy)-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]-naphthalen-2-yl-methanone{4-[2-(4-Chloro-phenoxy)-ethoxy]-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl}-naphthalen-2-yl-methanoneCarbonic acid ethyl ester1-[2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethylester[2-Methyl-4-(2-piperidin-1-yl-ethoxy)-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl]-naphthalen-2-yl-methanone4-Chloro-benzoic acid5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclohexanecarboxylic acid5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Benzoic acid5-chloro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chloro-benzoic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclohexanecarboxylic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Benzoic acid6-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chloro-benzoic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Cyclohexanecarboxylic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Benzoic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Acetic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Phenoxy-acetic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester (4-Chloro-phenoxy)-acetic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester(5-Chloro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(5-Chloro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(6-Fluoro-4-methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(6-Fluoro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(6-Fluoro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(7-Fluoro-4-methoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(7-Fluoro-4-ethoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(7-Fluoro-4-propoxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-aceticacid methyl ester[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-aceticacid methyl ester2-[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-piperidin-1-yl-ethanone2-[7-Fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-1-(4-methyl-piperazin-1-yl)-ethanone1-(4-Benzyl-piperazin-1-yl)-2-[7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-yloxy]-ethanoneBenzenesulfonic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester Benzenesulfonic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chloro-benzenesulfonic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Methyl-benzenesulfonic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Cyano-benzenesulfonic acid2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Chloro-benzenesulfonic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Methyl-benzenesulfonic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester 4-Cyano-benzenesulfonic acid7-fluoro-2-methyl-3-(naphthalene-2-carbonyl)-1,1-dioxo-2H-benzo[e][1,2]thiazin-4-ylester(4-Hydroxy-2-methyl-1,1-dioxo-7-piperidin-1-yl-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(7-Dimethylamino-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(4-Hydroxy-2-methyl-1,1-dioxo-7-pyrrolidin-1-yl-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone[4-Hydroxy-2-methyl-1,1-dioxo-7-(4-phenyl-piperazin-1-yl)-2H-benzo[e][1,2]thiazin-3-yl]-naphthalen-2-yl-methanone(7-tertbutyl-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(naphthalen-2-yl)methanone(4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(3,4-dichlorophenyl)methanone(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(3,4-dichlorophenyl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(benzofuran-2-yl)methanone(4-Hydroxy-2-ethyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)(benzofuran-2-yl)methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone(7-Fluoro-4-hydroxy-2-methyl-1,1-dioxo-2H-benzo[e][1,2]thiazin-3-yl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone(2,3-Dihydro-benzofuran-5-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2,3-Dihydro-benzofuran-5-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanoneBenzo[1,3]dioxol-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanoneBenzo[1,3]dioxol-5-yl-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(4-hydroxy-2-ethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanoneBenzo[b]thiophen-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanoneBenzofuran-5-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-methyl-1H-benzoimidazol-5-yl)-methanoneBenzo[b]thiophen-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4-tert-Butyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(3-Bromo-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzonitrile(3,4-Dimethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-trifluoromethyl-phenyl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4-trifluoromethyl-phenyl)-methanoneAdamantan-2-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanoneChroman-6-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4-Chloro-3-trifluoromethyl-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(7-Bromo-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(7-Chloro-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(4-Hydroxy-2,7-dimethyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanoneBiphenyl-3-yl-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2′-Fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(3′-Fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4′-Fluoro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2′-Choro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(3′-Choro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4′-Choro-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2′-Methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(3′-Methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4′-Methyl-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(2′-Methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(3′-Methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4′-Methoxy-biphenyl-3-yl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3′-trifluoromethyl-biphenyl-3-yl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(4′-trifluoromethyl-biphenyl-3-yl)-methanone3′-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-biphenyl-3-carbonitrile3′-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-biphenyl-4-carbonitrile(4-Hydroxy-7-methanesulfonyl-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-naphthalen-2-yl-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(1-phenyl-cyclopropyl)-methanone1-[3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)phenyl]-ethanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-methanone3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzoicacid3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N-methyl-benzamide3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N,N-dimethyl-benzamideN-Ethyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N,N-diethyl-benzamideN-Cyclopropyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-carbonyl)-benzamideN-Cyclopropylmethyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-N-phenyl-benzamideN-Benzyl-3-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzamide3-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazine-3-carbonyl)-benzoicacid ethyl ester(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-3-yl-phenyl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-(3-pyridin-4-yl-phenyl)-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methyl-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(5-methyl-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methyl-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methyl-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(4-methoxy-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-fluoro-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(2-methoxy-pyridin-3-yl)-phenyl]-methanone(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-[3-(6-methoxy-pyridin-3-yl)-phenyl]-methanone(3-Chloro-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone(3-Fluoro-phenyl)-(4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-benzo[e][1,2]thiazin-3-yl)-methanone7. A method for preparing the compounds of general formula (Ia) whichcorresponds to formula I according to claim 1 wherein R₁ represents ahydrogen atom characterized in that an intermediate of general formula(IV) is condensed

wherein R₂, R₄, et R′₄ are defined according to claim 1, with anintermediate of general formula R₃—Y wherein R₃ is defined according toclaim 1 and Y represents a leaving group.
 8. A method for preparing thecompounds of general formula (Ib) which corresponds to formula Iaccording to claim 1, wherein R₁ is different from a hydrogen atomcharacterized in that an intermediate of general formula (Ia) iscondensed

wherein R₂, R₃, R₄, and R′₄ are defined according to claim 1, with anintermediate of general formula R₁—Z wherein R₁ is defined as earlierand Z represents a leaving group.
 9. A method for preparing thecompounds of general formula (Ic) which corresponds to formula Iaccording to claim 1 wherein R₁ represents (CH₂)_(n)NR₇R₈ or(CH₂)_(n)OR₆ characterized in that an intermediate of general formula(V) is condensed

wherein R₂, R₃, R₄, R′₄, n are defined according to claim 1 and X′represents a leaving group, with an intermediate of general formulaR₇R₈NH or R₆OH wherein R₇, R₈ and R₆ are defined according to claim 1.10. A method for preparing the compounds of general formula (Id) whichcorresponds to formula I according to claim 1 wherein R₁ represents(CH₂)_(n)CONR₇R₈ characterized in that an intermediate of generalformula (VII) is condensed

wherein R₂, R₃, R₄, R′₄ and m are defined according to claim 1, with anintermediate of general formula R₇R₈NH wherein R₇ and R₈ are definedaccording to claim
 1. 11. A method for preparing the compounds ofgeneral formula (If) which corresponds to formula I according to claim 1wherein R₄ represents NR₇R₈ characterized in that an intermediate ofgeneral formula (Ie) is condensed

wherein R₂, R₃, and R′₄ are defined according to claim 1, with anintermediate of general formula R₇R₈NH wherein R₇ and R₈ are definedaccording to claim
 1. 12. A method for preparing the compounds ofgeneral formula (Ih) which corresponds to formula I according to claim 1wherein R₂ represents a biphenyl or phenyl pyridine either substitutedor not, characterized in that an intermediate of general formula (Ig) iscondensed

wherein R₃, R₄, R′₄ are defined according to claim 1 and X represents aleaving group, with a boronic acid.
 13. A method for preparing thecompounds of general formula (Ik) which corresponds to formula Iaccording to claim 1 wherein R₂ represents a phenyl substituted with anamide in the ortho or meta position characterized in that anintermediate of general formula (Ij) is condensed

wherein R₃, R₄, R′₄ are defined according to claim 1, with an amine ofgeneral formula R₇R₁₁NH wherein R₇ and R₁₁ are defined according toclaim
 1. 14. The compounds according to claim 1 for their use as drugs.15. Pharmaceutical compositions containing as an active ingredient atleast one compound according to claim 1, in combination with apharmaceutically acceptable carrier, as drugs.
 16. The pharmaceuticalcompositions according to claim 15 as an inhibitor of type 111β-hydroxysteroid dehydrogenase (11βHSD1).
 17. The pharmaceuticalcompositions according to claim 15 for both curative and preventivetreatment of diabetes of type
 2. 18. The pharmaceutical compositionsaccording to claim 15, for the both curative and preventive treatment ofdisorders related to type 1 11β-hydroxysteroid dehydrogenase (11βHSD1);or of obesity; or dyslipidemias; or arterial hypertension; oratherosclerosis and clinical pathologies which result therefrom such ascoronary strokes, or cerebro-vascular strokes or arteritis of the lowerlimbs; or hyperglycemias; or intolerance to glucose; orinsulin-resistance; or hypertriglyceridemias; or hypercholesterolemias;or restenoses; or pancreatitises; or retinopathies; or nephropathies; orneuropathies; or certain types of cancer or glaucomas.
 19. Thepharmaceutical compositions according to claim 15 in combination with apharmaceutically acceptable carrier and administered in association withan anti-diabetic agent such as biguanides, various forms of insulin,sulfonylureas, meglitinides, PPAR modulators, alpha-glucosidaseinhibitors, GLP-1 analogs, DPP-4 inhibitors, amyline analogs.
 20. Thepharmaceutical compositions according to claim 15 in combination with apharmaceutically acceptable carrier and administered in association withan anti-obesity agent such as for example orlistat or sibutramine.